Genetics
дополнительные статьи

Genetic Center
Filatov's Child Clinical Hospital © 2001-2004
Vladimir Solonichenko MD, Clinical Geneticist,©
E-mail:

06.24.2004

	REFERENCES - FIRST PUBLICATIONS 2000	ABSTRACTS
1	Adderson EE, Viskochil DH, Carey JC, Shigeoka AO, Christenson JC, Bohnsack JF, Hill HR. Growth failure, intracranial calcifications, acquired pancytopenia, and unusual humoral immunodeficiency: A genetic syndrome? Am J Med Genet 2000 Nov 6;95(1):17-20	We report on two children who may represent a novel syndrome consisting of a deficiency of immunoglobulin-bearing B lymphocytes and serum antibody, deficient intrauterine and/or postnatal growth, in-tracranial calcifications, and acquired pancytopenia. Poor growth, intracranial calcifications, developmental delay, and hematological abnormalities are common manifestations of congenital infection. However, humoral immunodeficiency is not characteristic in these infections, and no infection was found on extensive evaluation. Rare genetic syndromes may mimic intrauterine infections and may also include immunodeficiency. However the children reported here lack important characteristics or share distinctive manifestations not described in these disorders. Infants presenting with apparent congenital infections in whom a specific infectious cause cannot be identified should be followed carefully with immunological evaluations since this disorder may be progressive and considerable morbidity is attributable to hematological and immunological manifestations.
2	Aguirre-Aquino BI, Rogers DG, Traboulsi EI. A patient with de morsier and duane syndromes. J AAPOS 2000 Aug;4(4):243-5	de Morsier syndrome, or septo-optic dysplasia, is a developmental malformation complex characterized by optic nerve hypoplasia, dysgenesis of the septum pellucidum, and hypothalamic-pituitary dysfunction. (1,2) In Duane retraction syndrome, there is absence of the sixth nerve nucleus with congenital retraction of the globe and narrowing of the lid fissure in adduction, frequent abduction deficiency, and variable limitation to adduction of the affected eye. (3) The purpose of this report is to present a patient with the uncommon and previously unreported concurrence of both of these congenital malformation complexes, presumably because of a common disturbance of neuronal development.
3	Al-Gazali LI, Bakir M, Hamid ZM, Nair DK, Haas D, Amirlak I, Rushdi A. A new syndrome of optic nerve colobomas and renal abnormalities associated with arthrogryposis multiplex.Clin Dysmorphol 2000 Jul;9(3):183-188	Renal-coloboma syndrome is a developmental disorder involving optic nerve colobomas and renal hypoplasia/insufficiency, which exhibits autosomal dominant inheritance and a highly variable phenotype (OMIM:120330). Mutation in the PAX2 gene was found to result in the renal-coloboma phenotype. We report on an Arab family with autosomal dominant inheritance of a syndrome characterized by a variable combination of optic nerve colobomas, renal abnormalities, vesicoureteral reflux, lax joints and arthrogryposis multiplex. Apart from the arthrogryposis multiplex which has not been described in the renal-coloboma syndrome, the features of the syndrome in this family are very similar to the renal-coloboma syndrome. However sequencing of all 12 axons of PAX2 gene revealed no mutation in this family. The disorder in this family is likely to represent a new syndrome with features overlapping with the renal-coloboma syndrome.
4	Al-Gazali LI; Bakir M; Hamid ZM; Nath R; Haas D. Congenital bowing of the long bones associated with camptodactyly, talipes equinovarus and agenesis of the corpus callosum. Clin Dysmorphol 2000 Apr;9(2):93-97	We report a baby with congenital bowing of the long bones, camptodactyly, talipes equinovarus and radiological features resembling both Stuve-Wiedemann syndrome and Schwartz-Jampel syndrome type 2. The baby had, in addition, agenesis of the corpus callosum. This feature has not been reported in either of these syndromes. It is possible that this baby has a previously undescribed syndrome.
5	Al-Mayouf SM, Majeed M, Hugosson C, Bahabri S. New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome. Am J Med Genet 2000 Jul 3;93(1):5-10	We describe 10 patients (6 females and 4 males) from 6 unrelated families with an autosomal recessive disease characterized by simultaneous presentation of nodulosis, arthropathy and osteolysis. They were followed up regularly at King Faisal Specialist Hospital and Research Center in Saudi Arabia for clinical evaluation, serial blood work-up, and evaluating radiological changes. Nodulosis and arthropathy were the clinical criteria for inclusion in this study, and the ten patients fulfilled these criteria. All patients had nodulosis and distal arthropathy. Eight patients (80%) presented with deformed hands and four (40%) with painful hands. All patients had parents who were first cousins and three families had more than one affected child, the finding suggesting autosomal recessive inheritance. Osteopenia and undertubulation of bones distally more than proximally, and upper limbs affected more often than lower limbs, were found in all patients. Osteolysis was seen in carpal and tarsal bones. Other common findings were sclerotic cranial sutures, brachycephaly, and broad medial clavicles. This novel phenotype should be considered in the differential diagnosis of chronic arthritis. Familial arthropathies are more often seen in communities where interfamilial marriage is common. Such a collection of patients is ideal for homozygosity mapping of the disease locus.
6	Amiel, ]eanne; Faivre, L; Le Merrer, M.; Munnich, A.; Lyonnet, S.; Cormier-Daire, V. Dysmorphism, variable overgrowth, normal bone age and severe developmental delay: a 'Sotos-like' syndrome? Eur J Hum Genet 2000, v.8.Supplement 1,P-133	Sotos syndrome (SS, MIM157550) is a multiple congenital anomaly/ mental retardation/overgrowth syndrome of unknown origin characterised by facial dysmorphism, pre and post-natal over-growth, macrocephaly, advanced bone age and mild to moderate developmental delay. The mode of inheritance is likely autosomal dominant with a vast majority of cases being sporadic. This rela-tively common gestalt syndrome is probably overdiagnosed. Here, we report 5 unrelated patients (1 female and 4 males aged 2 to 13 years) with high forehead, frontal bossing, long face with pointed chin, hypertelorism, severe developmental delay, and normal bone age. Growth and OFC were variable (weight: +1.5 to +4 SD, height: +1 SD to +2.5 SD, OFC: +1.5 to +4 SD). Mild, non-specific ventricu-lomegaly was found in 4/5, thin corpus callosum in 1/5, kyphosis and pes planus in 4/5 cases. All patients have normal chromo-somes. Although each of these patients show a Sotos gestalt, we believe that severe developmental delay together with variable, but never major overgrowth, and normal bone age make SS diagnosis doubtful. We propose a "Sotos-like" syndrome and review patients reported as SS that could be included in that category.
7	Aslan Yakup, Erol Erduran, Necmettin Kutlu. Autosomal recessive multiple pterygium syndrome: A new variant? Am. J. Med. Genet. 93(3):194-197, 2000	Multiple pterygium syndromes include at least 15 different entities characterized by multiple pterygia or webs of the skin and multiple congenital anomalies. We describe a female infant who presented with a distinct constellation of multiple anomalies consisting of pterygia of the inguinal, intercrural and popliteal areas, flexion contractures and arthrogryposis of some joints, craniofacial anomalies including ectropion, medial canthal web, blepharophimosis, hypoplasia of nose, oral and nasopharyngeal cavities, vocal cords and tongue, micrognathia, orolabial synechiae secondary to pterygia, low set ears, alopecia, sad and expressionless face, short neck, asymmetric nipples, anal stenosis, rectal polyp, hypoplastic labia majora, complete syndactyly of all fingers and toes, pes equinovarus, band-like web between feet, and absence of the nails and phalangeal-palmar creases. Radiological examination showed synostosis, absence or hypoplasia of metacarpal, metatarsal and phalangeal bones on feet and hands, and hypoplasia of pelvic bones and scapulae. This pattern of anomalies does not fit entirely any of the known multiple pter- ygium syndromes. Autosomal recessive inheritance is most likely due to the presence of three similarly affected siblings and normal parents.
8	Bacino Carlos A, David W. Stockton, Roberta A. Sierra, Heidi A. Heilstedt, Raymond Lewandowski, Ignatia B. Van den Veyver. Terminal osseous dysplasia and pigmentary defects: Clinical characterization of a novel male lethal X-linked syndrome. Am. J. Med. Genet. 94(2):102-112, 2000	We describe a new syndrome of distal limb anomalies and pigmentary skin defects in 10 females of a large, four-generation pedigree. The family was ascertained through a 4-month-old infant girl with multiple anomalies, including hypertelorism, iris colobomas, low-set ears, midface hypoplasia, punched-out pigmentary abnormalities over the face and scalp, generalized brachydactyly, and digital fibromatosis. No affected males were identified in this pedigree. Affected females had a lower than normal male-to-female ratio of liveborn offspring, and some of them also had a history of several miscarriages. These findings, together with a significant variability in the phenotype of the affected females, suggest that this condition is inherited in an X-linked dominant fashion, with prenatal male lethality, and that X-inactivation plays an important role in the phenotypic expression of the disease. The syndrome has been described twice in the literature, but only in sporadic cases; it was therefore not recognized as a mendelian entity. Because the most consistent findings are anomalies of the distal skeleton of the limbs and localized pigmentary abnormalities of the skin, we named the syndrome terminal osseous dysplasia with pigmentary defects. This condition, though rare, can be added to the small group of male lethal X-linked dominant disorders in humans.
9	Basel D; Goldblatt J. Tibial aplasia--VACTERL association, a new syndrome? Clin Dysmorphol 2000 Jul;9(3):205-208	We report on a male infant, born to nonconsanguineous parents, with a vertebral anomaly, cardiac defect, tracheo-oesophageal fistula and hypospadias (VACTERL association) together with bilateral tibial aplasia. This pattern of abnormalities appears to represent a unique syndrome.
10	Berg J; Grace E; Teik KW; Hammond H; Tidman M; Fitz Patrick D. Bullous ichthyosiform erythroderma, developmental delay, aortic and pulmonary stenosis in association with a FRA12A. Clin Dysmorphol 2000 Jul;9(3):213-219	We present an 11-year-old female with bullous ichthyosiform erythroderma (BIE), learning disability, patent ductus arteriosus and mild stenosis of the aortic and pulmonary arteries. Chromosome analysis showed the expression of the rare folate-sensitive fragile site FRA12A at 12q13 in 8/20 (40%) of blood lymphocytes cultured in folate-deficient medium in the presence of trimethoprim. Her mother and maternal grandmother are phenotypically normal, but her mother shows expression of the same fragile site in 4/20 (20%) of cells cultured under the same conditions. Lymphocytes from the grandmother only showed expression of the fragile site when cultured in the presence of methotrexate in folate deficient medium. Interestingly, two genes (keratin 1 and keratin 2e) which are known to cause BIE map to 12q13. Molecular data is presented excluding three candidate (CCG)n repeats within keratin 1 gene. We present a review of previously reported FRA12A cases and discuss possible molecular explanations for the clinical findings in this patient.
11	Blair EM, Walsh S, Oldridge M, Wall SA, Wilkie AO. Newly recognised craniosynostosis syndrome that does not map to known disease loci. Am J Med Genet 2000 Nov 6;95(1):4-9	We describe a consanguineous family of Pakistani origin with five sibs, three of whom were affected by craniosynostosis of variable presentation. In addition, they had other congenital abnormalities principally affecting neurological, ocular, and limb development. We provide linkage evidence using intragenic and flanking microsatellite markers suggesting that the disease in this family was not caused by a mutation in one of the known craniosynostosis loci (FGFR1, FGFR2, FGFR3, MSX2, TWIST). Given the clinical novelty and parental consanguinity, we hypothesise that the affected individuals were autozygous for a recessively inherited mutation, at a novel locus, predisposing to craniosynostosis.
12	Blonchet, Patricia; Roubertie, A; Lefort, G; Le Merrer, M; Sarda, P. A new MCA/MR syndrome with severe spondyloepiphyseal dysplasia and cerebral anomalie. Eur J Hum Genet 2000, v.8.Supplement 1, P-256	We report on four sibs with an apparently unreported syndrome of severe spondyloepiphyseal dysplasia associated with cerebral anomalies. The non consanguinous Portuguese parents have a first healthy boy. The second pregnancy with monozygotic female twins was terminated because of hydrocephaly and cerebral calcifications in both foetuses. One of the foetuses presented flat dysplastic acetabulae on skeletal X-rays. The third pregnancy was terminated because of corpus callosum agenesis and ventriculomegaly in a male foetus. During the fourth pregnancy, no foetal anomaly was detected. A healthy boy with a normal cerebral ultrasound was born. At seven months, hypotonia and psychomotor retardation were noted. Metabolic and karyotype analyses were normal. Cerebral MRI revealed ventriculomegaly and cerebral atrophy. Skeletal X-rays diagnosed severe spondyloepiphyseal dysplasia with odontoid hypoplasia, platyspondyly, dysplastic iliae with a lacey border of iliac crests, irregular metaphysis, extreme brachy-dactyly with irregular metaphysis on the hands and feet, and small irregular carpal and tarsal bones. Although the radiographic and neurological findings in these sibs have some similarity to possible cases of severe Dyggve Melchior Clausen syndrome (Khosravi 1998), the precocity and severity of the phenjtype suggest a new bone dysplasia-CNS anomaly syndrome inherited as an autosomal recessive trait.
13	Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000 Jul 15;356(9225):213-7	BACKGROUND: Hereditary angioedema (HAE) is a well defined autosomal dominant disease (Mendelian Inheritance in Man #106100) that results from an inherited deficiency of C1 (the activated first component of complement) inhibitor function. We report an unusual variant of HAE with normal biochemical C1-inhibitor function, occurring only in women. METHODS: We screened 574 patients with recurrent angioedema of the skin for presence of HAE. 283 patients were selected, in whom angioedema was associated with abdominal pain attacks or recurrent life-threatening episodes of upper-airway obstruction, or both, rather than with urticaria. We measured C1-inhibitor concentration and functional activity as well as complement C4 concentration and took pedigrees to characterise patients. FINDINGS: 94 HAE cases with C1-inhibitor deficiency, positive family history, or both were identified. Biochemical testing showed that 84 patients from 49 families had a functional C1-inhibitor deficiency. 11 of these patients had no affected family members (probably representing de-novo mutations). Ten women with HAE, from ten families, had normal C1-inhibitor protein concentrations and function, and normal C4 concentration. A more detailed study of these families identified another 26 affected members, who were also all women. Of those women, 14 could be studied and also had normal C1-inhibitor concentration and function. The disease was seen in successive generations, and in offspring of affected mothers, the sex ratio (M/F) was shifted to 1/1.5. INTERPRETATION: HAE with normal C1-inhibitor concentration and function represents a unique genetic disease arising only in women. The formal genetics of this entity are suggestive of an X-linked dominant mode of inheritance. For this disorder we propose the term hereditary angioedema type 3 (HAE III).
14	Boute, Odile; Devisme, L; Moerman, A.; Coeslier, A.; Robert, Y.; Manouvrier, S. Familial neuronal migration disorder and coarse face. Eur J Hum Genet 2000, v.8.Supplement 1, P-137	We describe sibling with an hitertho non described neuronal migra-tion disorder and coarse face. There are born of healthy, unrelated parents. The first child, a three-years-old boy, presented with severe convulsivant encephalopathy, microcephaly of prenatal onset, dys-morphic features ( bitemporal retraction, synophris, epicanthus, anteverted nares, dysplastic ears, macroglossia, gingival hypertrophy, short webbed neck). Brain MRI showed diffuse polymicrogyria, corpus callosum hypoplasia and normal cerebellum. Blood karyotype and metabolic explorations were normal. During a further pregnancy ultrasound examination at 30 weeks of gestation revealed isolated microcephaly in a female fetus. Fetal neuroimaging showed polymicrogyria and the pregnancy was medically interrupted. The fetus presented with microcephaly and coarse face. Autopsy showed micrencephaly, diffuse microgyria saving only the anterior area of the temporal lobes and the posterior area of the occipital lobes, a small vacuolated corpus callosum and normal cerebellum. Histopathological examination revealed polymicrogyria associated with complex migration disorders. Several type of polymicrogyria have been described, usually due to sporadic post-migration, destructive disorders. Rare cases of familial polymicrogyria have been reported, but their findings differ from those we describe suggesting that this sibship represent a new syndrome with a possible autosomal recessive mode of inheritance.
15	Breuning M.H., A.P. Oranje, R.A.Th.M. Langemeijer, S.E.R. Hovius, A.F.M. Diepstraten, J.C. den Hollander, N. Baumgartner, J.R. Dwek, A. Sommer, H. Toriello. Recurrent digital fibroma, focal dermal hypoplasia, and limb malformations. Am. J. Med. Genet. 94:91-101, 2000	Recurrent digital fibroma of infancy generally is considered a sporadic tumor of childhood. We describe the case of a mother with recurrent digital fibroma at a young age who gave birth to a daughter with focal dermal hypoplasia, coloboma of the iris and eyelids, anal atresia, and extensive limb malformations. When the infant was 3 months old, fibromas started to appear at the fingertips. The cases of three additional patients are described, with a similar combination of multiple digital fibromas, pigmented marks on the temporal region, and limb malformations. One of these patients has consanguineous parents. The clinical findings overlap partially with Gorlin-Goltz syndrome, which has been renamed by some authors microphthalmia with linear skin defects (MLS). Since the skin signs are clearly different, however - more like those of Setleis syndrome (forceps mark temporal dysplasia) - the patients described here seem to have a new combination of congenital malformations. Deletion of distal Xp, known to occur in some MLS patients, was not detected using cosmids in fluorescence in situ hybridization. This pattern of digital fibroma with congenital malformations seems to represent a new syndrome.
16	Cabezas David A., Rachel Slaugh, Fatima Abidi, J Fernando Arena, Roger E Stevenson, Charles E Schwartz, Herbert A Lubs. A new X linked mental retardation (XLMR) syndrome with short stature, small testes, muscle wasting, and tremor localises to Xq24-q25. J Med Genet 2000;37:658-662	METHODSA large family is described in which mental retardation segregates as an X linked trait. Six affected males in three generations were studied by linkage and clinical examination.RESULTSCharacteristic clinical features include short stature, prominent lower lip, small testes, muscle wasting of the lower legs, kyphosis, joint hyperextensibility, abnormal gait, tremor, and decreased fine motor coordination. Affected subjects also had impaired speech and decreased attention span. A carrier female was mildly affected. A similar disorder was not found on review of our XLMR Database of 124 syndromes. Linkage analysis of 37 markers resulted in a lod score of 2.80 at DXS1212 and 2.76 at DXS425. The limiting markers were DXS424 and DXS1047. Ten of 124 XLMR syndromes and eight of 58 MRX families overlap this region.CONCLUSIONS.In summary, this family appears to have a new XLMR syndrome localising to Xq24-q25.
17	Cefle, Kivanc; Ozturk, S.; Palanduz, S.; Tanakol, R.; Turkmen, D.; Kir, N.; ВауШ, С.; Boz Erten,; A/if Koran, M.; Tascioglu, C.; Serakinci, N. Two sisters with hemifacial microsomia associated with possible polyglandular autoimmune syndrome type I. Eur J Hum Genet 2000, v.8.Supplement 1, P-151	Here we describe two sisters with features of hemifacial microsomia and polyglandular autoimmune syndrome type I. The proband, a 40 year-old woman had a history of hearing difficulty, secondary amenorrhoea, and gradual loss of vision. Physical examination showed severe asymmetric auricular malformation, mandibular deviation and diffuse vitiligo. Blood chemistry revealed hypo-calcemia and hyperphosphatemia. The parathyroid hormon level was low (1.0 pg/ml) and serum gonadotropin, oestradiol and progesteron levels were compatible with primary hypogonadism. Ophtalmological examination revealed pigmentary retinopathy, a complication of vitiligo. Adrenal autoantibodies were positive, although an ACTH stimulation test was normal. The sister of the proband had a history of primary amenorrhoea and hearing diffi-culty. She had localized vitiligo on the foreneck, mandibular deviation, asymmetric auricular malformation and preauricular tags. Serum calcium level was normal, while hormon levels were compatible with primary hypogonadism. The dysmorphic findings described in our patients are compatible with a diagnosis of hemi-facial microsomia. On the other hand, the constellation of other findings in the proband and in her syster (hypoparathyroidism, primary hypogonadism, vitiligo and adrenal antibodies) suggest polyglandular autoimmune syndrome type I. To our knowledge, this association has not been described before.
18	Cincinnati P; Midi P; Rutiloni C. Klippel-Feil syndrome, thenar hypoplasia, carpal anomalies and situs inversus viscerum. Clin Dysmorphol 2000 Oct;9(4):291-292	A 27-year-old female is described with Klippel-Feil syndrome, thenar hypoplasia, carpal anomalies and situs inversus viscerum. Other anomalies occurring with Klippel-Feil syndrome are discussed.
19	Claes S, K. Devriendt, G. Van Goethem, L. Roelen, J. Meireleire, P. Raeymaekers, J.J. Cassiman, J.P. Fryns. Novel syndromic form of X-linked complicated spastic paraplegia. Am. J. Med. Genet. 94(1):1-4, 2000	This study presents a family with a syndromic form of X-linked mental retardation in which four males in two generations present severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia. Multipoint linkage analysis with 24 highly polymorphic markers indicated two possible candidate regions: Xp21.1-Xq21.3 (flanking markers DXS1214 and DXS990) and Xq23-Xq27.1 (flanking markers DXS8020 and DXS984). The two known loci for X-linked mental retardation and spastic paraplegia are excluded: proteolipid protein in Xp21 and L1 cell adhesion molecule in Xq28. Therefore, the syndrome in this family appears to represent a previously undescribed X-linked spastic paraplegia-mental retardation syndrome.
20	Devriendt K; Keymolen K; Roelen L; Van Goethem G; Meireleire J; Fryns JP. Severe short stature, hyperphalangy of the index fingers, mental retardation and facial dysmorphism. Clin Dysmorphol 2000 Apr;9(2):111-114	We present an adult female patient with a so far unreported syndrome of severe short stature, severe mental retardation, facial dysmorphism and hyperphalangy of the index fingers. Parental consanguinity suggests an autosomal recessive inheritance.
21	Elliott AM, Teebi AS. New autosomal dominant syndrome reminiscent of Coffin-Siris syndrome and Brachymorphism-Onychodysplasia-Dysphalangism syndrome.Clin Dysmorphol 2000 Jan 9:1 15-9	We report a man and his two daughters (one stillborn) with an apparently unique constellation of anomalies including fifth finger/toe terminal phalanx and nail hypoplasia. The craniofacial manifestations include large boxy head, round face, hypertelorism with downslanting palpebral fissures and wide mouth. Other manifestations include brachydactyly, fifth finger clinodactyly and ventricular septal defect. Intelligence is normal. The resemblance to Coffin-Siris, Brachymorphism-Onychodysplasia-Dysphalangism and DOOR syndromes is discussed and we concluded that this family probably represents a new autosomal dominant syndrome.
22	Farooqi IS, Jones MK, Evans M, O'Rahilly S, Hodges JR.Triple H syndrome: a novel autoimmune endocrinopathy characterized by dysfunction of the hippocampus, hair follicle, and hypothalamic-pituitary adrenal axis. J Clin Endocrinol Metab 2000 Aug;85(8):2644-8	No abstract available.
23	Fryns JP, Aftimos S. New MR/MCA syndrome with distinct facial appearance and general habitus, broad and webbed neck, hypoplastic inverted nipples, epilepsy, and pachygyria of the frontal lobes. J Med Genet 2000 Jun;37(6):460-2 (letter)	No abstract available.
24	Gabrielli O; Carloni I; Cordiali R; Bruschi B; Rocchi E; Coppa GV. Peculiar facies, obesity, cleft lip and palate, growth hormone deficiency and mental retardation: a new syndrome? Clin Dysmorphol 2000 Apr;9(2):153-154	A female child with peculiar facies, obesity, cleft lip and palate, growth hormone deficiency and mental retardation is described. The present case does not appear to fit any of the known syndromes.
25	Glorieux FH, Rauch F, Plotkin H, Ward L, Travers R, Roughley P, Lalic L, Glorieux DF, Fassier F, Bishop NJ. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 2000 Sep;15(9):1650-8	Osteogenesis imperfecta (OI) is commonly subdivided into four clinical types. Among these, OI type IV clearly represents a heterogeneous group of disorders. Here we describe 7 OI patients (3 girls), who would typically be classified as having OI type IV but who can be distinguished from other type IV patients. We propose to call this disease entity OI type V. These children had a history of moderate to severe increased fragility of long bones and vertebral bodies. Four patients had experienced at least one episode of hyperplastic callus formation. The family history was positive for OI in 3 patients, with an autosomal dominant pattern of inheritance. All type V patients had limitations in the range of pronation/supination in one or both forearms, associated with a radiologically apparent calcification of the interosseous membrane. Three patients had anterior dislocation of the radial head. A radiodense metaphyseal band immediately adjacent to the growth plate was a constant feature in growing patients. Lumbar spine bone mineral density was low and similar to age-matched patients with OI type IV. None of the type V patients presented blue sclerae or dentinogenesis imperfecta, but ligamentous laxity was similar to that in patients with OI type IV. Levels of biochemical markers of bone metabolism generally were within the reference range, but serum alkaline phosphatase and urinary collagen type I N-telopeptide excretion increased markedly during periods of active hyperplastic callus formation. Qualitative histology of iliac biopsy specimens showed that lamellae were arranged in an irregular fashion or had a meshlike appearance. Quantitative histomorphometry revealed decreased amounts of cortical and cancellous bone, like in OI type IV. However, in contrast to OI type IV, parameters that reflect remodeling activation on cancellous bone were mostly normal in OI type V, while parameters reflecting bone formation processes in individual remodeling sites were clearly decreased. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations affecting glycine codons or splice sites. In conclusion, OI type V is a new form of autosomal dominant OI, which does not appear to be associated with collagen type I mutations. The genetic defect underlying this disease remains to be elucidated.
26	Gobello Tommaso, Cinzia Mazzanti, Giovanna Zambruno, Luca Massimo Chinni, Rudolf Happle. New Type of Epidermal Nevus Syndrome. Dermatology 201:1:2000, 51-53	An uncommon type of epidermal nevus characterized by systematized bands of non-epidermolytic hyperkeratosis with increased hairiness and follicular hyperkeratosis was observed in a 16-year-old boy who showed, in addition, hemihypoplasia of limbs, brachydactyly, clinodactyly and onychodystrophy. This case cannot be categorized within the group of presently established epidermal nevus syndromes. Most likely, this combination of anomalies represents a new type of epidermal nevus syndrome.
27	Gohlich-Ratmann G, Lackner A, Schaper J, Voit T, Gillessen-Kaesbach G. Syndrome of gingival hypertrophy, hirsutism, mental retardation and brachymetacarpia in two sisters: specific entity or variant of a described condition? Am J Med Genet 2000 Nov 27;95(3):241-6	Two sisters born to consanguineous Lebanese parents had mental retardation and epilepsy, brachymetacarpalia, hirsutism, bulbous soft nose, thick floppy ears with abnormal configuration and gingival hypertrophy. One girl presented additionally with tetralogy of Fallot and the other with congenital hypothyroidism and bilateral ureteral stenosis. These manifestations resemble the syndrome of hypertrichosis-gingival fibromatosis-mental retardation and seizures of Anavi et al. [1989: Dev Med Child Neurol 31:538-542] but our two girls additionally have brachymetacarpia. The inheritance seems to be autosomal recessive. These two sisters may represent a hitherto undescribed syndrome. We discuss the findings in our patients in relation to the literature.
28	Guerreiro MM; Andermann E; Guerrini R; Dobyns WB; Kuzniecky R; Silver K; Van Bogaert P; Gillain C; David P; Ambrosetto G; Rosati A; Bartolomei F; Parmeggiani A; Paetau R; Salonen O; Ignatius J; Borgatti R; Zucca C; Bastos AC; Palmini A; Fernandes W; Montenegro MA; Cendes F; Andermann F. Familial perisylvian polymicrogyria: a new familial syndrome of cortical maldevelopment. Ann Neurol 2000 Jul;48(1):39-48	Two familial X-linked dominant syndromes of cortical maldevelopment have recently been described: double cortex/lissencephaly syndrome and bilateral periventricular nodular heterotopia. We report on 12 kindreds with familial perisylvian polymicrogyria (FPP) presenting at 10 centers, examine the clinical presentation in these familial cases, and propose a possible mode of inheritance. The clinical and radiological pattern was variable among the 42 patients, with clinical differences among the families and even within members of the same family. Pseudobulbar signs, cognitive deficits, epilepsy, and perisylvian abnormalities on imaging studies were not found in all patients. When present, they displayed a spectrum of severity. The only clear correlation in this study was between bilateral imaging findings and abnormal tongue movements and/or pronounced dysarthria. Most of the families provided evidence suggestive of, or compatible with, X-linked transmission. On the other hand, the pedigrees of 2 families ruled out X-linked inheritance. The most likely mode of inheritance for these 2 families was autosomal dominant with decreased penetrance; however, autosomal recessive inheritance with pseudodominance could not be ruled out in 1 family. We conclude that FPP appears to be genetically heterogeneous. However, most of the families probably represent a third previously undescribed X-linked syndrome of cortical maldevelopment.
29	Guion-Almeida ML; Richieri-Costa A. Amniotic band sequence versus the autosomal recessive microcephaly, facial clefting, and preaxial polydactyly syndrome. Clin Dysmorphol 2000 Oct;9(4):297-299	We report a Brazilian boy, born to consanguineous parents. On the left arm there was a proximal 'ring shaped' constriction, regional aplasia cutis, and a short hand with markedly hypoplastic fingers and nails 2-3. He also had a bilateral cleft lip/palate, preaxial polydactyly involving the distal phalanx of the left index finger, and a supernumerary nipple on the right. The differential diagnosis is discussed.
30	Gul D, Oktenli C, Saglam M, Erdem U. Craniofacial anomalies, ocular findings, pigmented nevi, camptodactyly, and skeletal changes: a possible new autosomal recessive disorder. Clin Dysmorphol 2000 Jan;9(1):61-2	A 20-year-old male is described with craniofacial anomalies, ocular findings, pigmented nevi, camptodactyly and skeletal changes. On the basis of the clinical and radiological differences with syndromes previously described we classify the present case as a new faciothoracoskeletal syndrome. Parental consanguinity supports autosomal recessive inheritance.
31	Gul D; Odabas E; Kutlu M. Oculocutaneous albinism and reduced bone density in two sibs: a new autosomal recessive syndrome? Clin Dysmorphol 2000 Oct;9(4):295-296	A sister and brother, with oculocutaneous albinism and reduced bone density are described. Autosomal recessive inheritance is possible. This association has not been previously described.
32	Haftel LT, Lev D, Barash V, Gutman A, Bujanover Y, Lerman-Sagie T. Familial mitochondrial intestinal pseudo-obstruction and neurogenic bladder. J Child Neurol 2000 Jun;15(6):386-9	Intestinal dysmotility and neurogenic bladder have been described as part of two autosomal-recessive mitochondrial disorders assumed to be due to a defect in communication between the nuclear and mitochondrial genomes: myoneurogastrointestinal encephalopathy (MNGIE) and diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome). Partial cytochrome c oxidase deficiency has been described in both. We describe three Ashkenazi Jewish siblings with progressive intestinal dysmotility, neurogenic bladder, and autonomic manifestations but no central nervous system involvement. Cytochrome c oxidase deficiency was demonstrated in peripheral and multiple intestinal muscle biopsies. Mitochondrial DNA analysis of an intestinal biopsy of patient 1 showed heteroplasmy consisting of a normal 16.5-kb band and an approximately 28-kb band, suggestive of a duplication. Mitochondrial DNA analysis of a muscle biopsy of patient 2 showed multiple deletions, mainly 10- and 11-kb bands. We suggest that this unique combination of intestinal pseudo-obstruction and neurogenic bladder could comprise a new autosomal-recessive mitochondrial disorder.
33	Hilhorst-Hofstee Y; Shah N; Atherton D; Harper JI; Milla P; Winter RM. Radial aplasia, poikiloderma and auto-immune enterocolitis--new syndrome or severe form of Rothmund-Thomson syndrome? Clin Dysmorphol 2000 Apr;9(2):79-85	A syndrome is described in three isolated patients in whom the main features are bilateral radial aplasia, short stature, an inflammatory based 'elastic' pyloric stenosis, a pan-enteric inflammatory gut disorder that appears to be due to an autoimmune process, and poikiloderma. Other features in individual cases include cleft palate, micrognathia, anal atresia, patellar aplasia/hypoplasia and sensorineural deafness. This combination may represent a severe form of Rothmund-Thomson syndrome or possibly a previously unrecognized condition.
34	Holinski-Feder Elke, Edwin Reyniers, Sabine Uhrig, Astrid Golla, Jan Wauters, Peter Kroisel, Paul Bossuyt, Imma Rost, Kerry Jedele, Hannelore Zierler, Sieglinde Schwab, Dieter Wildenauer, Michael R. Speicher, Patrick J. Willems, Thomas Meitinger, and R. Frank Kooy. Familial Mental Retardation Syndrome ATR-16 Due to an Inherited Cryptic Subtelomeric Translocation, t(3;16)(q29;p13.3) Am. J. Hum. Genet., 66:16-25, 2000	IIn the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%10% of cases.
35	Intiso D, Cioffi R, Di Viesti P, Simone P, Tonali P. Bilateral periventricular nodular heterotopia associated with coeliac disease and palatoschisis. Ital J Neurol Sci 1998 Jun;19(3):180-3	Periventricular nodular heterotopia (PNH) is considered a distinct entity in relation to the other forms of neuronal migration disorders (NMD), because PNH patients usually have normal neurological and mental examination results. We report the case of a 48-year-old woman with bilateral periventricular nodular heterotopia associated with epilepsy, coeliac disease, palatoschisis and other dysmorphic features. Her intelligence quotient (I.Q.) and the results of a neurological examination were normal, but she suffered from a drug-resistant epileptic syndrome characterised by predominantly generalised and sporadic partial seizures. It has recently been suggested that an X-linked dominant inheritance may play a role in bilateral periventricular nodular heterotopia, and it is thought that a genetic defect is probably responsible for coeliac disease. In our patient, a genetic disorder may have produced both diseases and the dysmorphic syndrome, although the coexistence of PNH, epileptic seizures, coeliac disease and palatoschisis could be coincidental. Further observations are needed to ascertain whether the simultaneous presence of these disorders is simply an unusual association of unrelated pathologies or a new and distinct pathological entity.
36	Jarrah Nadim, Hatem El-Shanti, Ahmad Khier , Fatima Nouri Obeida, Azmi Haddidi, Kamel Ajlouni. Familial disorder of sex determination in seven individuals from three related sibships. Eur J Pediatrics, 2000,159(12):912-918	In humans, the sex of an individual is determined by the Y-chromosome-related SRY gene, which causes the differentiation of the undifferentiated gonads into testicular tissue. True hermaphrodites without a Y chromosome and XX males represent a sex determination error in which testicular tissue develops despite the absence of the SRY gene. Familial forms of XX true hermaphrodites and XX males exist in the literature, which also contains the two forms co-existing in the same family. In this report, we present a large family with seven affected individuals with phenotypes ranging from XX male to XX true hermaphrodite with predominance of female characteristics. We suggest that XX maleness and XX true hermaphroditism represent a continuum of the same disorder. We speculate on the mode of inheritance of this disorder in this particular family.
37	Kajantie E; Pirinen S; Tommiska V; Kaitila I. A syndrome with midface asymmetry, defective modelling of the skeleton, catch-up growth and truncal obesity. Clin Dysmorphol 2000 Oct;9(4):259-264	We report follow-up from birth up to 16 years of age of a patient with a previously undescribed combination of dysmorphic features. These include: intrauterine growth retardation developing to normal adult stature with truncal obesity, asymmetry of the midface skeleton with severe orthodontic problems, brachydactyly of the hands and feet, wide medial phalanges of the fingers, partial soft tissue syndactyly, simian creases and normal mental development. We consider other differential diagnoses and suggest that the patient represents a hitherto undescribed syndrome.
38	Kirel B, Kural N, Yakut A, Adapinar B. Triplets with growth failure, microcephaly, mental retardation, nail hypoplasia and corpus callosum agenesis: is it a variant of Coffin-Siris or a new syndrome? Turk J Pediatr 2000 Apr-Jun;42(2):171-6	We report eight-year-old triplet girls whose clinical features included microcephaly, severe mental retardation, hypoplasia of distal phalanges of both fifth and second fingers and nail hypoplasia on second fingers, dysmorphic facial features, and partial corpus callosum agenesis. During infancy, a Pavlik harness was used for congenital hip dislocation, and they had difficulty in feeding. One had been operated for patent ductus arteriosus. To our knowledge, this rare combination has not been previously reported in triplets whose clinical features closely resemble those of Coffin-Siris syndrome. The other diagnostic possibilities are also reviewed.
39	Knight-Jones E, Knight S, Heussler H, Regan R, Flint J, Martin K. Neurodevelopmental profile of a new dysmorphic syndrome associated with submicroscopic partial deletion of 1p36.3. Dev Med Child Neurol 2000 Mar;42(3):201-6	We describe four children with dysmorphic syndrome with severe learning disability (SLD). Their chromosomes had been normal on conventional cytogenetic examination. However, screening using a multiprobe fluorescence in situ hybridisation (FISH) technique for subtelomeric abnormalities revealed a deletion of the p arm of chromosome 1. The physical features include body asymmetry, microcephaly, distinctive facies with deep-set eyes, sharply defined eye sockets, and mid-face hypoplasia; the neurodevelopmental profile was characterised by SLD, motor delay with hypotonia, markedly delayed visual maturation, and postural asymmetry together with epilepsy. This phenotype is consistent with that described for partial monosomy for 1p36.3.
40	Krause MH, Bonnekoh B, Weisshaar E, Gollnick H. Coincidence of multiple, disseminated, tardive-eruptive blue nevi with cutis marmorata teleangiectatica congenita. Dermatology 2000 200:2 134-8	A 71-year-old woman reported a slow progression of multiple bluish dark asymptomatic macules and papules on the pretibial region of both lower legs for over 30 years. At birth a left-sided hypoplasia of the leg including the buttock accompanied by a connatal vascular nevus had been diagnosed. The ipsilateral deep veins of the pelvis and leg had a normal anlage. Histopathological examination revealed multiple blue nevi of the common type. The association of multiple blue nevi and cutis marmorata teleangiectatica congenita with limb hypoplasia has not previously been reported and is discussed in this paper. One could speculate whether these symptoms represent a new syndrome, because by thorough examination the NAME syndrome could be ruled out.
41	Kuhnle U, Bartsch O, Werner W, Schuster T. Penoscrotal inversion, hypospadias, imperforate anus, facial anomalies, and developmental delay: definition of a new clinical syndrome. Pediatr Surg Int 2000;16(5-6):396-9	We describe a 2-month-old boy with penoscrotal inversion, hypospadias, imperforate anus, facial anomalies, developmental retardation, and a subtelomeric deletion of chromosome 13q. His phenotype with anogenital malformations and characteristic facies closely resembled two unrelated patients with minute deletions of chromosome 13q who we reported earlier. In addition, he had unilateral renal agenesis. We propose that these patients represent a clinically recognizable, novel chromosomal microdeletion syndrome. The findings indicate the presence of a major gene(s) on chromosome 13q33.2qter that regulate(s) the migration and development of ano-reno-genital cells and organs. We speculate that mutations of this developmental gene(s) may also result in more frequent congenital malformations (isolated hypospadias, uterus bicornis, unilateral renal agenesis). Additional studies are needed to further delineate the genetic defect.
42	Leblanc R. Familial adenomatous polyposis and benign intracranial tumors: a new variant of Gardner's syndrome. Can J Neurol Sci 2000 Nov;27(4):341-6	INTRODUCTION: Familial adenomatous polyposis (FAP) is associated with malignant tumors of the central nervous system, predominantly medulloblastomas and glioblastoma multiforme (Turcot's syndrome) and with craniofacial osteomas (Gardner's syndrome). This report details the occurrence of benign, intracranial tumors in two related individuals with Gardner's syndrome, an association not previously described. PATIENTS AND METHODS: A 57-year-old woman (the propositus), her sister, two of her nieces and one of her grandnephews were previously diagnosed with Gardner's syndrome. The propositus came to neurosurgical attention because of vertigo associated with what proved to be an epidermoid cyst of the cerebellopontine angle. Her unaffected children and her relatives with Gardner's syndrome were examined and underwent computed tomography or magnetic resonance imaging. RESULTS: A 39-year-old woman with Gardner's syndrome, the niece of the propositus, was found to harbor an asymptomatic left frontal meningioma. DISCUSSION: Familial adenomatous polyposis, Gardner's syndrome, and that variant of Turcot's syndrome in which medulloblastoma predominate, are associated with a mutation of the adenomatous polyposis coli gene. The demonstration that patients with Gardner's syndrome can also have benign, nonneuroglial, intracranial tumors adds to the previously known extracolonic lesions associated with FAP. The molecular characterization of our patients should reveal if benign intracranial tumors represent a pleiotropic manifestation of the adenomatous polyposis coli gene mutation or if other genes are implicated.
43	LEV Dorit, MIRIAM YANOOV, SHLOMO WEINTRAUB, TALLY LERMAN-SAGIE. Progressive neurological deterioration in a child with distal arthrogryposis and whistling face. J Med Genet 2000;37:231-233 (Letter)	We describe a child who presented from birth with distal arthrogryposis, profound mental retardation, severe hypotonia, and whistling face. The severe neurological involvement precludes him from having FSS according to the classification of Bamshad et al.(1996). We suggest that patients with a whistling face, distal contractures, and severe neurological involvement should be diagnosed as having a separate autosomal recessive syndrome.
44	Loeys, Bart; Schrander-Stumpel, C.; De Paepe, A. Persistent ductus Botalli associated with ascending aorticaneurysm and clubfoot in two families: a new autosomal dominant entity? Eur J Hum Genet 2000, v.8.Supplement 1,	We present two unrelated, female probands with persistent ductus arteriosus and aneurysm of the ascending aorta. First patient (28y) had two sisters who died from aortic dissection and both had previous surgical repair of open ductus Botalli. Her father died at age 63 years from aortic dissection. Second patient (21m) has one sister (5y) with open ductus arteriosus, aortic dilatation and clubfoot. None of the affected individuals has other features of Marfan syn-drome or Ehlers-Danlos syndrome, except for soft skin in the second patient. cDNA screening of the FBN-1 (fibrillin 1) gene in the first patient with heteroduplex, SSCP and CSGE revealed no abnormalities. In family 2 linkage with FBN-1, but not with COL3A1 was excluded. However, COL3A1 mutation screening by SSCP was normal. CSGE screening of the COL3A1 gene and linkage analysis and/or mutation analysis of the FBN-2 in family 2 are ongoing. We found only one report in the literature of a three years old boy with persistent ductus arteriosus and multiple arterial aneurysmsclassified as an unknown EDS type.
45	Mahbubul Huq AH, Nigro MA. XY sex reversal and a nonprogressive neurologic disorder: a new syndrome? Pediatr Neurol 2000 Oct 1;23(4):357-360	We report a patient with a unique combination of clinical findings: XY sex reversal, spastic paraplegia, mental retardation, dysmorphism, and infantile-onset olivopontocerebellar hypoplasia. The phenotype of our patient did not coincide with any of the described forms of XY reversal syndromes, hereditary or sporadic spastic paraplegias, or congenital or infantile-onset cerebellar or olivopontocerebellar atrophies or hypoplasias. The disorder of this patient likely represents a genetic condition with pleiotropic effects on brain development and sex determination and adds further evidence for the heterogeneity of spastic paraplegia/infantile olivopontocerebellar hypoplasia syndromes and sex reversal syndromes.
46	Manouvrier S, Moerman A, Coeslier A, Devisme L, Boute O, Le Merrer M. Radioulnar synostosis, radial ray abnormalities, and severe malformations in the male: a new X-linked dominant multiple congenital anomalies syndrome? Am J Med Genet 2000 Feb 28;90(5):351-5	We describe a multiple congenital anomalies (MCA) syndrome dominantly transmitted through three generations. Radial ray abnormalities with wide variability of expression were observed in four female patients. Moreover, a 14-week-gestation male fetus had severe radial ray malformation, anencephaly, unilateral renal agenesis, and a common dorsal mesentery. Results of high-resolution karyotyping were normal in the malformed fetus and his affected mother. Furthermore, several spontaneous abortions of male fetuses had occurred in this pedigree. To our knowledge, a similar association has not been described previously. It could represent a new X-linked dominant MCA syndrome, or an autosomal dominant condition with severe expression limited to males.
47	Marcano Ana Carolina Braga, Antonio Richieri-Costa. A Newly Recognized Autosomal Dominant Mandibulofacial Dysostosis (Bauru Type): Report on a Brazilian Family. The Brazilian Journal of Dysmorphology and Speech-Hearing Disorders, vol.1, №2	We report on a Brazilian family with 5 affected patients presenting with malar hypoplasia, cleft lip/palate, micrognathia, mild down-slanting palpebral fissures and abnormal ears. These patients may have an undescribed autosomal dominant syndrome within the group of the mandibulofacial dysostosis.
48	Malchoff CD, Sarfarazi M, Tendler B, Forouhar F, Whalen G, Joshi V, Arnold A, Malchoff DM. Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome. J Clin Endocrinol Metab 2000 May;85(5):1758-64	Papillary thyroid carcinoma usually is sporadic, but may occur in a familial form. The complete clinical and pathological phenotype of familial papillary thyroid carcinoma (fPTC) has not been determined, and the susceptibility gene(s) is unknown. We investigated the clinical and pathological characteristics of an unusually large three-generation fPTC kindred to characterize more fully the clinical phenotype. We performed linkage analysis to determine the chromosomal location of a fPTC susceptibility gene. In addition to the known association of fPTC with nodular thyroid disease, we observed the otherwise rare entity of papillary renal neoplasia (PRN) in two kindred members, one affected with PTC and the other an obligate carrier. The multifocality of PRN in one subject adds weight to the likelihood of a true genetic predisposition to PRN. Both genetic linkage and sequence analysis excluded MET, the protooncogene of isolated familial PRN, as the cause of the fPTC/PRN phenotype. A genome-wide screening and an investigation of specific candidate genes demonstrated that the fPTC/PRN phenotype was linked to 1q21. A maximum three-point log of likelihood ratio score of 3.58 was observed for markers D1S2343 and D1S2345 and for markers D1S2343 and D1S305. Critical recombination events limited the region of linkage to approximately 20 cM. A distinct inherited tumor syndrome has been characterized as the familial association of papillary thyroid cancer, nodular thyroid disease, and papillary renal neoplasia. The predisposing gene in a large kindred with this syndrome has been mapped to 1q21.
49	Martin DM, Probst FJ, Camper SA, Petty EM. Characterisation and genetic mapping of a new X linked deafness syndrome. J Med Genet 2000 Nov;37(11):836-841	BACKGROUND: Hereditary forms of hearing loss are classified as syndromic, when deafness is associated with other clinical features, or non-syndromic, when deafness occurs without other clinical features. Many types of syndromic deafness have been described, some of which have been mapped to specific chromosomal regions. METHODS: Here we describe a family with progressive sensorineural hearing loss, cognitive impairment, facial dysmorphism, and variable other features, transmitted by apparent X linked recessive inheritance. Haplotype analysis of PCR products spanning the X chromosome and direct sequencing of candidate genes were used to begin characterising the molecular basis of features transmitted in this family. Comparison to known syndromes involving deafness, mental retardation, facial dysmorphism, and other clinical features was performed by review of published reports and personal discussions. RESULTS: Genetic mapping places the candidate locus for this syndrome within a 48 cM region on Xq1-21. Candidate genes including COL4A5, DIAPH, and POU3F4 were excluded by clinical and molecular analyses. CONCLUSIONS: The constellation of clinical findings in this family (deafness, cognitive impairment, facial dysmorphism, variable renal and genitourinary abnormalities, and late onset pancytopenia), along with a shared haplotype on Xq1-21, suggests that this represents a new form of syndromic deafness. We discuss our findings in comparison to several other syndromic and non-syndromic deafness loci that have been mapped to the X chromosome.
50	Megarbane A; Melki I; Souraty N; Gerbaka J; El Ghouzzi V; Bonaventure J; Mornand A; Loiselet J. Overlap between Baller-Gerold and Rothmund-Thomson syndrome. Clin Dysmorphol 2000 Oct;9(4):303-305	We report a male patient with craniosysnostosis, bilateral radial and ulnar hypoplasia, absent thumbs, poikiloderma, and short stature. His parents are first cousins. Although this patient was originally diagnosed as having Baller-Gerold syndrome it is more likely that he has Rothmund-Thomson syndrome or a similar disorder. This report confirms the overlap between these two syndromes, and that Baller-Gerold syndrome is essentially a diagnosis of exclusion.
51	Mehndiratta MM, Agarwal P, Sharma A, Agarwal S. Dandy Walker Syndrome Associated with Unusual Congenital Anomalies.Indian Pediatr 2000 Aug 7;37(8):896-898	No abstract available.
52	Montgomery TL; Wyllie J; Oley C. Ectrodactyly and glaucoma associated with a 7q21.2-q31.2 interstitial deletion. Clin Dysmorphol 2000 Oct;9(4):235-239	An infant with ectrodactyly, glaucoma, cleft palate, congenital heart defect and genital anomalies associated with a 7(q21.2q31.2) deletion is presented. Glaucoma and ectrodactyly in association with a 7q deletion has not been previously reported. We recommend that early ophthalmological assessment is required in infants with such deletions.
53	Nanke Y, Kotake S, Akama H, Usuda S, Tateishi M, Yamagata H, Kamatani N. Multiple dislocations of distal interphalangeal joints associated with interstitial pneumonia and Sjogren's syndrome: a possible new complex. J Rheumatol 2000 Jul;27(7):1798-800 (ynn@murayama.hosp.go.jp)	No abstract available.
54	Ng D, Stratakis CA. Premature adrenal cortical dysfunction in mandibuloacral dysplasia: A progeroid-like syndrome. Am J Med Genet 2000 Nov 27;95(3):293-5	No abstract available.
55	Nye Jeffrey S., Erin A. Hayes, Michael Amendola, Daleik Vaughn , Joel Charrow, David G. Mclone, Marcy C. Speer, Walter E. Nance, Arti Pandya. Myelocystocele-cloacal exstrophy in a pedigree with a mitochondrial 12S rRNA mutation, aminoglycoside-induced deafness, pigmentary disturbances, and spinal anomalies. Teratology 61:165-171, 2000.	A large Filipino-American family with progressive matrilineal hearing loss, premature graying, depigmented patches, and digital anomalies was ascertained through a survey of a spina bifida clinic for neural crest disorders. Deafness followed a matrilineal pattern of inheritance and was associated with the A1555G mutation in the 12S rRNA gene (MTRNR1) in affected individuals as well as unaffected maternal relatives. Several other malformations were found in carriers of the mutation. The proband had a myelocystocele, Arnold-Chiari type I malformation, cloacal exstrophy, and severe early-onset hearing loss. Several family members had premature graying, white forelock, congenital leukoderma with or without telecanthus, somewhat suggestive of a Waardenburg syndrome variant. In addition to the patient with myelocystocele, two individuals had scoliosis and one had segmentation defects of spinal vertebrae. The syndromic characteristics reported here are novel for the mitochondrial A1555G substitution, and may result from dysfunction of mitochondrial genes during early development. However, the mitochondrial A1555G mutation is only rarely associated with neural tube defects as it was not found in a screen of 218 additional individuals with spina bifida, four of whom had congenital hearing loss.
56	Ogur, Gonul; Laleye, A.; Delneste, D. Association of osteopetrosis, short stature, optical atrophy and female sterility: a new variant of dominant osteopetrosis or a new syndrome. Eur J Hum Genet 2000, v.8.Supplement 1,	Osteopetrosis is a rare metabolic bone disorder manifested by variable increase in skeletal mass. It was first described by Albers-Schonberg in 1904 and since than several cases have been reported. Albers-Schonberg disease is the classical autosomal dominant form of osteopetrosis. It results from a failure of bone resorption and is characterized by a generalized sclerosis of bone. The skull base is usually involved; loss of vision with optic nerve atrophy is the most common neurological finding. The etiology and relevantmutations of the disease is still unknown. Primary sterility is not a well defined characteristic of human osteopetrosis and is not yet, to our knowledge, mentioned as a feature of the A-S disease. Recently a role for growth factor colony-stimulating factor-1 (CSF-1) in female reproduction was confirmed by studies on CSF-1 deficient, osteopetrotic (csfmop/csfmop) mice. Here we report a an 18 year-old black, female patient with osteosclerosis of the skull base, proportionate short stature, optic atrophy and primary amenorrhea.Clinical and biochemical aspects with respect to literature data of osteosclerosis have been discussed. We suggest it to be a new syndrome or a new variant of dominant osteopetrosis.
57	Olander Erika, Judith Stamberg, Lisa Steinberg, Eric A. Wulfsberg. Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15. Am. J. Med. Genet. 93(3):215-218, 2000	We report on a boy with mosaicism for trisomy 15 and Prader-Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype-genotype differences are useful to guide the work-up of patients with suspected PWS and to provide prognostic counseling for families.
58	Orme L, Gorlick R, Meyers PA, Athanasian E, Huvos AG. Osteosarcoma associated with absent thumbs: a report of two cases. J Pediatr Hematol Oncol 2000 Jan-Feb;22(1):73-7	An 8-year-old Hispanic boy with a hypoplastic left thumb, absent right thumb, and short stature experienced right leg pain and limp. A right tibial lesion was imaged and found to be osteosarcoma on biopsy. A 6-year-old Hispanic girl with congenitally absent thumbs experienced a pathologic fracture of her left femur after a minor sports injury. The radiologic abnormality seen was diagnosed as osteosarcoma on biopsy. Both patients continue to do well after intensive preoperative and postoperative high-dose chemotherapy and definitive reconstructive limb surgery. Osteosarcoma has been linked to several congenital syndromes in which absent thumbs are a feature. These two patients with absent thumbs and no definable syndrome experiencing osteosarcoma suggest that congenitally absent thumbs might be a risk factor for osteosarcoma in the absence of a syndrome.
59	Ozden,; Duzcan, F.; Sahiner, T.; Bayromoglu, I. Autosomal dominant progressive optic atrophy and hearing loss in three generations of a family. Eur J Hum Genet 2000, v.8.Supplement 1, P-249	Ten members in 3 generations of a family with progressive optic atrophy and also progressive hearing loss are described. The mode of inheritance is clearly autosomal dominant. Exceptionally, two younger members of the family had only optic atrophy without deafness and four persons had blepharochalasis in addition to the main features. The proband, a 9 years old boy, was complained of progressive visual failure admitted to Ophthalmology Department. According to family history his mother, an aunt and two uncles, grandfather and 3 of the cousins also have had progressive visual and hearing loss; whereas his half-sister had only optic atrophy as proband. Both of the complaints of affected persons were told to start between the ages of 7 and 10. Six affected persons and 3 unaf-fected ones were examined in detail. Optic atrophy and deafness has been reported in a number of syndromes as the main features, although most of these syndromes were associated with various neurological and myopathic features. None of the members in this family showed evidence of having any of these disorders, however 4 of them had blepharochalasis.
60	Ozkinay F, Cogulu O, Akil I, Gunduz C, Ozkinay C. Fronto-facio-nasal dysplasia in two sisters with additional findings. Acta Paediatr 2000 Sep;89(9):1145-7	No abstract available.
61	Pavone L, Rizzo R, Pavone P, Curatolo P, Dobyns WB. Diffuse polymicrogyria associated with congenital hydrocephalus, craniosynostosis, severe mental retardation, and minor facial and genital anomalies. J Child Neurol 2000 Jul;15(7):493-5	We report an infant boy with an apparently new malformation syndrome. The major anomalies showed by the patient include diffuse polymicrogyria, congenital hydrocephalus, craniosynostosis with severe scaphocephaly, severe mental retardation, intractable epilepsy, and minor facial and genital anomalies. Our review of the literature and two computerized dysmorphology databases found some papers reporting polymicrogyria or lissencephaly associated with craniosynostosis or hydrocephalus. None of the reported patients had a phenotype similar to that of our patient.
62	Pavone P, Parano E, Polizzi A, Trifiletti RR. Colobomatous microphthalmia, microcephaly with cerebellar hypoplasia: association or new syndrome? Am J Med Genet 2000 Jun 5 92(4):278-80	We report on a 3.5-year-old girl with microcephaly, microphthalmia, coloboma of the iris, mild developmental delay, and other minor anomalies. Neuroimaging showed marked cerebellar and vermian hypoplasia. This condition has not been described previously and is discussed in the context of the ''micro syndrome,'' together with other similar syndromes. Our case highlights the heterogeneity of the ''microphthalmia plus brain malformations'' group of patients.
63	Plomp AS; Reardon W; Benton S; Taylor D; Larcher VF; Sundrum R; Winter RM. An unknown combination of infantile spasms, retinal lesions, facial dysmorphism and limb abnormalities. Clin Dysmorphol 2000 Jul;9(3):189-192	A female patient is presented with infantile spasms, punched-out retinal lesions, facial dysmorphism, short upper arms, short thumbs, left lower limb hypoplasia with foot deformity, a hemivertebra, atrial septal defect, growth retardation and severe developmental delay. There is some similarity to patients with Aicardi syndrome (AS), but the retinal lesions in our patient are different and she does not have agenesis of the corpus callosum, one of the diagnostic features of AS. She might represent an atypical form of this syndrome with additional features, usually not present in AS. As there is no diagnostic test for AS yet, this diagnosis cannot be confirmed nor rejected with certainty. However, it might be more likely that our patient has another, possibly unique, condition.
64	Potgieter Steph, Gert Matthijs, Paul De Cock, Jean-Pierre Fryns. Preaxial polydactyly type 1 and severe language deficit in maternal uniparental disomy of chromosome 7 Eur J Pediatr,2000,159(12):929-929 (correspondence)	No abstract available.
65	Priolo M; Lerone M; Rosaia L; Calcagno EP; Sadeghi AK; Ghezzi F; Ravazzolo R; Silengo M. Question mark ears, temporo-mandibular joint malformation and hypotonia: auriculo-condylar syndrome or a distinct entity? Clin Dysmorphol 2000 Oct;9(4):277-280	We report a boy with prominent, peculiarly malformed ears, abnormality of the ramus of the mandible and hypotonia. An isolated peculiar bilateral ear deformity named 'question mark ear' has been delineated in plastic reconstruction surgery reviews [Cosman et al., 1970 Plast Reconstr Surg 46:454-457; Cosman (1984) Plast Reconstr Surg 73:572-576; Takato et al. (1989) Ann Plast Surg 22:69-73; Brodovsky (1997) Plast Reconstr Surg 100:1254-1257; Park (1998) Plast Reconstr Surg 101:1620-1623; Al-Quattan (1998) Plast Reconstr Surg 102:439-441] and a similar deformity of the ear and changes in the temporo-mandibular joint and condyle has been described by Jampol et al. [(1998) Am J Med Genet 75:449-452] and by Guion-Almeida et al. [(1999) Am J Med Genet 86:130-133]. The present case may be the third description of this malformation complex with additional clinical features characterized by hypotonia and mild developmental delay, or possibly a new distinct entity.
66	Quadrelli R, Vaglio A, Reyno S, Lemes A, Salazar D, Lachman RS, Wilcox WR. Uruguay facio-cardio-musculo-skeletal syndrome: A novel X-linked recessive disorder. Am J Med Genet 2000 Nov 27;95(3):247-65	We report on three male patients from a single family with a brachyturricephaly, "pugilistic" facial appearance, a muffled voice, cardiomyopathy, muscular hypertrophy, broad hands, wide feet with progressive pes cavus deformities, dislocation of toes, variable congenital hip dislocation, and scoliosis. Three other males in the family, now deceased from cardiac disease, appear to have had the same disorder. The mother of the propositus has milder signs of the syndrome. All affected males are related through the maternal line. These cases represent an apparently previously undescribed X-linked recessive syndrome.
67	Ramanan AV; Hussain K; Hird M; Gaspar HB. Short limbed skeletal dysplasia associated with combined immunodeficiency and congenital subglottic stenosis: a new constellation of features. Clin Dysmorphol 2000 Jul;9(3):173-176	A newborn male is described with an association of short limbed dwarfism with hip dislocation, combined immunodeficiency characterized by absent B cells and CD4 lymphopaenia and congenital subglottic stenosis. This constellation of abnormalities is distinct from other described skeletal dysplasias associated with immunodeficiency such as ADA deficiency and cartilage hair hypoplasia.
68	Ramos-Arroyo MA, Valiente A, Rodriguez-Toral E, Alonso AM, Moreno S, Weaver DD. Familial choanal atresia with maxillary hypoplasia, prognathism, and hypodontia. Am J Med Genet 2000 Nov 27;95(3):237-40	We report on two sibs and a cousin with bilateral choanal atresia. At 2 months, one sib died of complications following surgical correction of her defects. We evaluated her brother and cousin at age 7 and 9 years, respectively. Both had a tall forehead, maxillary hypoplasia, prognathism, and absence of certain deciduous and permanent teeth. Psychomotor development was appropriate for age. Roentgenocephalometric analyses of several relatives showed that one grandfather of these children and two of the five uncles and aunts also had maxillary hypoplasia and/or prognathism. To our knowledge, this condition has not been described previously and may represent a newly recognized autosomal dominant condition with incomplete penetrance and variable expressivity caused by a defect of neural crest development.
69	Revy P, Busslinger M, Tashiro K, Arenzana F, Pillet P, Fischer A, Durandy A. A syndrome involving intrauterine growth retardation, microcephaly, cerebellar hypoplasia, B lymphocyte deficiency, and progressive pancytopenia. Pediatrics 2000 Mar;105(3):E39	We report a new complex syndrome involving profound failure to thrive with severe intrauterine growth retardation, cerebellar abnormalities, microcephaly, a complete lack of B lymphocyte development, and secondary, progressive marrow aplasia. B cell differentiation was found to be blocked at the pro-B cell stage. Although not strictly proven, a genetic origin is likely, according to similar cases reported in the literature. Three candidate genes, PAX5, encoding B cell-specific activator protein, a factor involved in B cell lineage commitment, stromal cell-derived factor 1, and CXCR4, encoding a chemokine and its receptor, respectively, were thought to be responsible for this disease, given the similarity between the phenotype of the corresponding knock-out mice and the clinical features of the patient. However, the genomic DNA sequences of these 3 genes were normal, and normal amounts of stromal cell-derived factor 1 and CXCR4 were present. These data strongly suggest that another molecule is involved in early B cell differentiation, hematopoiesis, and cerebellar development in humans.
70	Romeo MG; Nicoletti MC; Saporito A; Cilauro S; Romeo DM; Smilari P. Caudal regression syndrome and annular pancreas: a rare association. Clin Dysmorphol 2000 Oct;9(4):293-294	A female infant with caudal regression syndrome and annular pancreas is described. This is the first time this association appears to have been described.
71	Rossiter JP, Khalifa MM, Nag S. Diencephalic neuronal hamartoma associated with congenital obstructive hydrocephalus, anophthalmia, cleft lip and palate and severe mental retardation: a possible new syndrome. Acta Neuropathol (Berl) 2000 Jun;99(6):685-90	A male infant was born with severe hydrocephalus, bilateral cleft lip/palate, left anophthalmos and right microphthalmos, and an equino-varus foot deformity. Imaging studies showed enlarged lateral ventricles, apparent absence of the corpus callosum and a midline density in the third ventricular region. He had a normal male karyotype. He was severely mentally retarded and died suddenly at 7 years of age. Neuropathological examination of the brain revealed enlarged and polygyric cerebral hemispheres, due to congenital obstructive hydrocephalus, and secondary thinning of the corpus callosum. An unusually large neuronal hamartoma filled the interpeduncular fossa and third ventricle. It was continuous posteriorly with the left thalamus and so was classified as diencephalic rather than as hypothalamic. The right optic nerve merged with the hamartoma, whereas the left nerve was absent. Microscopically the hamartoma consisted of mature grey matter interspersed with narrow bands of white matter. No immature or non-neural elements were identified. This combination of diencephalic neuronal hamartoma, hydrocephalus, ocular and craniofacial abnormalities has not, to our knowledge, previously been described.
72	Ruggieri M, Rizzo R, Pavone P, Baieli S, Sorge G, Happle R Temporal Triangular Alopecia in Association With Mental Retardation and Epilepsy in a Mother and Daughter.Arch Dermatol 2000 Mar;136(3):426-7 (letter)	Temporal triangular alopecia (TTA) is a hair anomaly characterized by unilateral or, less frequently, bilateral, lancet-shaped or oval patches of permanent, nonscarring hairlessness in the frontotemporal region of the scalp with the apex usually extending to the vertex. We describe a mother and daughter, both with TTA in combination with neurological features; the daughter also had a Dandy-Walker malformation type B.
73	Sacha M. P. Koch, Shrawan Kumar, Cor W. R. J. Cremers. A Family With Autosomal Dominant Inherited Dysmorphic Small Auricles, Lip Pits, and Congenital Conductive Hearing Impairment. Arch Otolaryngol Head Neck Surg. 2000;126:639-644	Design We examined 3 generations in a family for congenital conductive hearing impairment, dysmorphic small auricles, and lip pits.Results Seven members of the family had bilateral dysmorphic auricles. Three subjects had either a pit or dimple in the lip. Two subjects had congenital conductive hearing impairment.Conclusion Using gene linkage, we confirmed that these autosomal dominant inherited branchial anomalies present a new separate branchial arch syndrome.
74	Savarirayan Ravi, Valérie Cormier-Daire, Cynthia J. Curry, Marcus B. Nashelsky, Valerie Rappaport, David L. Rimoin, Ralph S. Lachman. New mesomelic dysplasia with absent fibulae and triangular tibiae. Am. J. Med. Genet. 94(1):59-63, 2000	We report on two unrelated, sporadic cases of a mesomelic dysplasia characterized by absence of fibulae and severely hypoplastic, triangular-shaped tibiae. Moderate mesomelic shortness was present in the upper limbs with proximal widening of the ulnae. There was also axial skeletal involvement in both cases, characterized radiographically by an abnormal pelvis and marked bilateral glenoid hypoplasia. These cases appear to represent a new form of mesomelic dysplasia distinct from those previously delineated.
75	Schauder S, Hanefeld F, Noske UM, Zoll B. Depigmented hypertrichosis following Blaschko's lines associated with cerebral and ocular malformations: a new neurocutaneous, autosomal lethal gene syndrome from the group of epidermal naevus syndromes? Br J Dermatol 2000 Jun;142(6):1204-1207	The lines of Blaschko represent one of the cutaneous patterns of mosaicism followed by various skin disorders. Developmental abnormalities affecting other tissues derived from the embryonic ectoderm and mesoderm are occasionally associated. We describe a 30-year-old man with depigmented, bilateral hypertrichosis and dilated follicular orifices following Blaschko's lines associated with cerebral and ocular malformations. The findings suggest a previously unreported neurocutaneous, autosomal lethal gene syndrome from the group of epidermal naevus syndromes.
76	Schneider EN, Bogdanow A, Goodrich JT, Marion RW, Cohen MM Jr. Fronto-ocular syndrome: newly recognized trigonocephaly syndrome. Am. J. Med. Genet. 93(2):89-93, 2000	We describe an apparently unique disorder, Fronto-Ocular syndrome, present in a mother and her two daughters, and comprising trigonocephaly due to coronal and metopic craniosynostosis, ocular hypotelorism, ocular proptosis and ptosis, epicanthal folds, hypoplastic supraorbital ridges, elevated nasal bridge, thin philtrum, high-arched palate and a narrow bifrontal region. Both daughters have glabellar capillary hemangiomas, a congenital heart defect and mild developmental disabilities. Review of the literature failed to disclose any syndrome with similar findings. It is likely that this disorder represents an autosomal dominant condition, that arose as a new mutation in the mother. Mutational analysis of fibroblast growth factor receptor (FGFR) 1 and FGFR2 failed to identify the molecular basis of the disorder.
77	Semerci, Nur; Balcy, S.; Bebitoglu, I.; Kacar, A.; Yuttagul, S. ;Ercakmak, S.; Ertoy, D.; Ozaltyn, F.An unusual fetus with absence of thoracal, lumbal, sacral vertebrae and ribs, bilateral renal agenesis, VSD, a sacralmeningomyelocele, imperforate anus, teratoma. Is it a new entity? Eur J Hum Genet 2000, v.8.Supplement 1, P-105	This was the first child of a consangineous family: a 30 weeks of age male fetus. The mother was 18 years, the father 22 years old. The first admission of mother was at 30th week of the gestation and she had no previous prenatal obstetric follow-up. Ultrasono-graphy showed severe anhydramnios, generalized ascites, shortlimbs, ventriculomegaly and approximately 5 week intrauterin growth retardation. The family denied exposure to any teratogenic factor or radiation during the pregnancy. Delivery was induced and the fetus was born dead. The external appearence of the fetus was unusual: He had Potter facies, short contracted limbs, club foot, imperforate anus and a huge sacrococygeal cystic mass. Postmortem x-ray showed normal cervical vertebrae but total absence of thoracal, lumbal, sacral vertebrae and ribs. Autopsy findings: A single umblical arter, hemidiaphragm, VSD, complete ileal stenosis, blind ended large bowel, anal atresia, bilateral renal agenesis, retroperitoneal teratoma, meningomyelocele, enlarge-ment of lateral ventricul. The difficulty in the explanation of the associated malformations makes our case interesting and these malformation complex has not been reported previously. We believed that the cause of these malformation complex possibly due to the defect of developing the organs begin after 21 days of gestation.
78	Shalev, Stavit ; Mazor Galia, M.G.; Reich, R.D.; Shapira, S.Y. Zlotogora, ZJ. A congenital syndrome with developmental delay and unusual inheritance. Eur J Hum Genet 2000, v.8.Supplement 1,	In a large Muslim Arab kindred we diagnosed a same syndrome in sixteen members (9 males and 7 females). All these children were born to 6 healthy women closely related one to the other. The main clinical findings include hypotonia, micro-retrognathia, cleft palate, and feeding problems in infancy. Later in childhood growth retar-dation with slender appearance develops, with psychomotor delay and "myopathic face". The clinical features and the results of extensive laboratory testing did not allow us to classify the patients to any previously described syndrome. In particular we excluded an inherited chromosomal aberration including 15ql3 and 22qll microdeletions. Mitochondrial inheritance seems to be improbable because the presence of the syndrome only in one generation, the normal histology and mitochondrial enzymes. Autosomal recessive inheritance seems unlikely since 3 of the fathers are not related to the kindred, and there is an excess of affected individuals. Dominant inheritance may explain the obser-vations only if the penetrance is incomplete and if a particular mechanism explains that affected children are born only to carrier women, such as subtle translocation, a premutation or an imprinted gene.
79	Shetty AK, Chatters R, Tilton AH, Lacassie Y. Syndrome of microcephaly, mental retardation, and tracheoesophageal fistula associated with features of Rett syndrome.J Child Neurol 2000 Jan 15:1 61-3	We report a 12-year-old girl with features of the syndrome of microcephaly, mesobrachydactyly, and tracheoesophageal fistula, who also developed distinctive features of Rett syndrome including regression of milestones with repetitive actions, autistic-like behavior, stereotypic hand movements, and seizures. This unique combination of clinical manifestations appears to constitute a ''new syndrome.'' We speculate that this association may represent a contiguous gene syndrome.
80	Shintaku M, Y. Uemura, I. Fujii, Y. Ohtani, T. Miike, M. Tokunaga, A. Tsubura. Neuroaxonal leukodystrophy associated with congenital cutis laxa: report of an autopsy case. Acta Neuropathologica,99(4):420-424,2000	A male patient, who was born with congenital cutis laxa characterized by cutaneous laxity due to the degeneration of elastic fibers, presented with an arrest of mental and motor development at the age of 3 years. The progressive decline of the psychomotor abilities led to the patient's death at the age of 4 years and 9 months. An autopsy revealed extensive white matter degeneration, characterized by the formation of numerous neuroaxonal spheroids and a diffuse loss of axons and myelin sheaths. The centrum semiovale and the cerebellar white matter were the most severely affected. The ultrastructure of the spheroids was consistent with a dystrophic type of axonal swelling. Neurons of the cerebral cortex, cerebellar cortex, and some brain stem nuclei were lost in moderate to severe degrees, and there were relatively few neuroaxonal spheroids in the gray matter. The pallidum and substantia nigra were well preserved. Neuroaxonal leukodystrophy, in which the spheroid formation predominantly affects the white matter, is the rarest variant of primary neuroaxonal dystrophies, and there are very few reports of autopsied cases. Among the reported cases, two Japanese siblings had congenital skin lesions similar to those of our case. The unique association of neuroaxonal leukodystrophy and congenital cutis laxa may form a distinct variant in this disease category.
81	Smith A, Jauch A, Slater H, Robson L, Sandanam T. Syndromal obesity due to paternal duplication 6(q24.3-q27). Am J Med Genet 1999 May 21;84(2):125-31	The likelihood of a paternally expressing imprinted gene in chromosome region 6(q23-24) has been highlighted by cases of transient neonatal diabetes mellitus (TNDM) in which paternal uniparental disomy (UPD) for chromosome 6 or paternal duplication 6(q23-qter) was detected. We present the case of a 38-year-old man with moderate to severe intellectual delay, short stature, small hands and feet, eye abnormality, small mouth, and obesity (without hyperphagia) beginning in mid-childhood. The perinatal and neonatal histories were normal. The patient had a duplication within 6q. Fluorescence in situ hybrisation studies were performed with single and dual hybridisations using a chromosome 6 library probe, short and long arm subregional probes, 6q23-24, 6q25.3-6qter locus-specific probes, and a 6q telomere probe. The hybridisation results defined an inverted duplication of 6q24.3 to 6q27. DNA studies with microsatellite markers from 6p and 6q showed regular biparental inheritance of chromosome 6 and confirmed that the duplication was paternal in origin. Our patient appears to be the first one known to have paternal duplication of chromosome area 6(q24-q27) who did not have TNDM as an infant. He has remained nondiabetic, although obesity, without hyperphagia, has been a constant problem since its onset in mid-childhood.
82	Stephan E, Ashoush R, Megarbane A, Kassab R, Salem N, Loiselet J, Bouvagnet P. Autosomal dominant Mendelian midline complex. Secundum atrial septal defect associated with cardiac and facial-thoracic defects. A familial case. Arch Mal Coeur Vaiss 2000 May;93(5):641-7 [Article in French]	The kindred of 38 individuals reported here have various anomalies: 1. facio-thoracic malformations: hypertelorism, nasal deviation, cleft lip and palate, upper-incisors diastema and pectus excavatum; 2. cardiac anomalies: sinus node bradycardia, atrial fibrillation, nodal rhythm, atrial septal defect. Wolff-Parkinson-White syndrome, low insertion of the septal tricuspid valve corresponding to an Ebstein syndrome, pulmonic "en dome" valve stenosis, aortic valve stenosis, long QT, and intraventricular conduction blocks. Almost all these defects are septal or para-septal. Mitral stenosis is probably rheumatoid. Such median varied pathology has not been yet reported. All the extra-cardiac anomalies are situated along the vertical upper half-body midline. All cardiac anomalies are in the septal or para-septal region. It is an autosomal dominant trait that implies the early embryonic development of the midline of cardiac and extra-cardiac structures.
83	Stewart H; Kerr B; Tomlin P; Stacey D; Super M. Sibs with developmental delay, hirsutism and nail hypoplasia: a new syndrome. Clin Dysmorphol 2000 Oct;9(4):241-246	A sister and brother with developmental delay, hirsutism and variable nail hypoplasia are described. The facial features of these sibs are striking. We postulate that this represents a new syndrome, the inheritance of which is unknown.
84	Stratakis CA, Lafferty A, Taymans SE, Gafni RI, Meck JM, Blancato J. Anisomastia associated with interstitial duplication of chromosome 16, mental retardation, obesity, dysmorphic facies, and digital anomalies: molecular mapping of a new syndrome by fluorescent in situ hybridization and microsatellites to 16q13 (D16S419-D16S503). J Clin Endocrinol Metab 2000 Sep;85(9):3396-401	Anisomastia is a common problem among developing adolescent girls. We recently evaluated a 22-yr-old female patient who had severe anisomastia (which had been repaired by surgery), associated with moderate to severe mental retardation, a stocky body habitus with mild obesity, dysmorphic facies (prominent, upslanting palpebral fissures, beaked nose, and a prominent philtrum), webbed neck, low hairline, and severe bilateral clinodactyly of the third, fourth, and fifth fingers with acral (but not large joint) flexion contractures. A peripheral blood high resolution karyotype revealed additional chromosomal material within the long arm of chromosome 16. Densitometric analysis of amplified polymorphic sequence-tagged sites (STS) mapping to 16q suggested that the duplication is defined by the noninvolved markers D16S419 [16q12-cen, 66 centimorgan (cM) from 16p terminus] and D16S421 (16q13-q21, 84.4 cM), encompassing a maximum of 18.4 cM of genetic distance. The STS analysis showed that the duplication was on the maternally derived chromosome 16, resulting in two maternal (and one paternal) copies of that region of chromosome 16. The location was further confirmed by bacterial artificial chromosomes (BACs) that were obtained from a commercially available library, labeled, and used for fluorescence in situ hybridization. The BACs containing STSs D16S408, D16S3137, and D16S3032 (markers that correspond to 16q13) showed two regions of hybridization, indicating that these sites were duplicated, whereas a BAC containing the STS D16S512 (which corresponds to 16q21-q22) revealed one hybridization signal per 16q, indicating that the corresponding region was not involved in the duplication. The distance between the probe signals suggested a tandem duplication. We conclude that even though trisomy 16 is the most common autosomal trisomy in spontaneous abortions, few patients with unbalanced chromosome 16 abnormalities survive to adulthood; in this report we describe one such patient with an interstitial chromosome 16 duplication (at 16q13), who had a specific phenotype associated with abnormal breast size. There are clinical similarities between this patient and patients with other 16q abnormalities, although the breast findings were unique. Molecular cytogenetics, including fluorescence in situ hybridization and densitometric analysis of amplified STSs, provided useful tools for the precise mapping of the syndrome to 16q13, where the gene(s) responsible for this phenotype might be localized.
85	Tentlera Dmitry , Peter Gustavsson, Göran Elinder, Ole Eklöf, Laurie Gordon, Ariane Mandel, Niklas Dahl. A microdeletion in 19q13.2 associated with mental retardation, skeletal malformations, and Diamond-Blackfan anaemia suggests a novel contiguous gene syndrome. J Med Genet 2000;37:128-131	Diamond-Blackfan anaemia (DBA) is a constitutional red blood cell hypoplasia which may be associated with a variety of developmental abnormalities. A gene for DBA was recently mapped to chromosome 19q13.2 and subsequently cloned. Analysis of 19q marker alleles in DNA of sporadic DBA cases showed de novo microdeletions in three patients also presenting with mental retardation. We have studied one of these patients and characterised the deletion by fluorescence in situ hybridisation (FISH) to extended DNA fibres. The deletion was shown to be continuous over a 3.2 Mb region and the fibre-FISH analysis showed both chromosomal breakpoints. In combination, the clinical and molecular findings suggest a contiguous gene syndrome with a gene locus for mental retardation and, probably, skeletal malformations included in the deletion.
86	Toutain, Annick; Moizard, M.P.; Hommet, C. Spastic paraplegia, mental retardation and glaucoma in three siblings. A rare probably autosomal recessive syndrome. Eur J Hum Genet 2000, v.8.Supplement 1, P-152	We report on three brothers, born of consanguineous Algerian parents, who were affected with spastic paraplegia diagnosed in infancy, mild/moderate mental retardation and glaucoma. All three patients remained ambulatory at the age of 40, 37 and 24 respectively. Brain MRI, metabolic investigations and chromosome analysis were normal. Linkage to the genes XNP, PLP and L1CAM, known to be involved in syndromic X-linked spastic paraplegia, was excluded by DNA analysis. The clinical picture in this family is strikingly similar to that described in two previous families and further supports the existence of a distinct genetic entity charac-terized by the triad of spastic paraplegia, mental retardation and glaucoma. In this condition spastic paraplegia is diagnosed in infancy but there is no or very slow progression and no other neuro-logical signs. Mental retardation is mild or moderate and OFC is normal. Glaucoma is diagnosed in adulthood or late adolescence but is responsible for a severe visual impairment. Consanguinity in all three pedigrees, affected females in one of them and the results of the linkage analysis in the present family support auto-somal recessive inheritance.
87	Trevisan G, Pauluzzi P, Gatti A, Semeraro A. Familial mastocytosis associated with neurosensory deafness. J Eur Acad Dermatol Venereol 2000 Mar;14(2):119-22	Mastocytosis is a disease characterized by excessive accumulation of mast cells in different tissues and symptoms caused by the release of mast cell mediators. The skin is frequently directly involved in mastocytosis. The disease is rarely seen in other members of the subjects' family; only 49 cases of familial mastocytosis have been reported. Familial mastocytosis associated with hearing loss may represent a newly described inherited entity. We describe a brother and sister exhibiting skin mastocytosis and neurosensory deafness, associated with a history of hearing loss in their father's family. The appearance of the mast cell disease in two siblings, who presented with similar clinical features represents a familial form of mastocytosis; the association with an inherited form of deafness may constitute a new syndrome. Our patients show several features similar to some previously reported cases but different insofar that additional congenital defects and mental retardation are absent.
88	Van den Berg-Vos RM, Van den Berg LH, Franssen H, Vermeulen M, Witkamp TD, Jansen GH, van Es HW, Kerkhoff H, Wokke JH. Multifocal inflammatory demyelinating neuropathy: a distinct clinical entity? Neurology 2000 Jan 11;54(1):26-32	BACKGROUND: Several patients have been reported with an asymmetric sensory or sensorimotor demyelinating neuropathy not fulfilling the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy or multifocal motor neuropathy. OBJECTIVE: To present the clinical, electrophysiologic, radiologic, and pathologic features of six patients with an asymmetric sensory or sensorimotor demyelinating neuropathy. RESULTS: All six patients were initially affected in only one limb; in four patients the neuropathy progressed to other limbs in an asymmetric fashion during several years. On electrophysiologic examination, evidence of multifocal demyelination and conduction block in motor and sensory nerves was found in all patients. MRI of the brachial plexus revealed swollen nerves and an increased signal intensity on T2-weighted imaging in four patients. A biopsy sample taken from the brachial plexus of one patient revealed evidence of inflammation. All patients showed a beneficial response to IV immunoglobulin treatment. Thirty-four similar patients have been reported previously, many of whom were initially diagnosed as having various other (nontreatable) diseases. CONCLUSIONS: The authors propose calling this neuropathy "multifocal inflammatory demyelinating neuropathy" and considering it as a distinct clinical entity to facilitate early diagnosis of this treatable disorder.
89	van Nesselrooij, Bernadette; Dorland, L; Sinke, R.J.; Duran, M.; Beemen FA; Poll The, B.T. A novel X-linked mental retardation syndrome with extrapyramidal system involvement and post-prandial hyperaminoacidemia. Eur J Hum Genet 2000, v.8.Supplement 1, P-247	We present a family with 4 male patients, linked by healthy females, with choreoathetosis, spasticity, dystonia and severe mental retar-dation. The major specific biochemical abnormality was a striking post-prandial hyperaminoacidemia, mainly involving the neutral amino acids. In the index patient the neurologic abnormalities and mental retardation were evident at the age of six months. There were no dysmorphic features. Fundoscopy and a MRI scan of the brain were normal. Grossly elevated plasma levels were observed for alanine and glutamine, whereas several other amino acids were moderately increased. ОСТ deficiency was excluded. In the other investigated patients plasma analysis showed similar abnormalities. No clinical signs and normal plasma levels were found in obligate carriers and a healthy male relative. Linkage studies localise the disorder to a 25-cM interval between markers DXS6807 and DXS8049 on the short arm of the X-chromosome. Several aspecific mental retardation syndromes and some syn-dromes with neurologic features are mapped in this region of Xp22. However, the clinical picture and the metabolic abnormalities in our family are suggestive for a novel syndrome.
90	Vélez A. and J.-C. Moreno. Poland's syndrome and recessive X-linked ichthyosis in two brothers. Clinical & Experimental Dermatology 25 (4), 308-311	Poland's syndrome consists of unilateral congenital absence of the pectoralis major muscle with a variable degree of ipsilateral upper limb deformity. The aetiology of Poland's syndrome is unknown, although an inherited tendency to develop a compromised embryonic vascular supply in the affected areas has been suggested. The majority of reported cases are sporadic, and in only a few instances is there a familial incidence. We describe the occurrence of Poland's syndrome in two brothers who also had recessive X-linked ichthyosis. To the best of our knowledge this is the first report of such an association.
91	Verloes A; Lesenfants S. Agenesis of the corpus callosum, camptodactyly and obesity. Clin Dysmorphol 2000 Apr;9(2):107-109	We report a 16-year-old girl with agenesis of the corpus callosum, congenital heart disease (ventricular septal defect and abnormal venous return), 5th digit camptodactyly and obesity, born to first cousin Italian parents. Although this child shares features with acrocallosal syndrome and Camera-Marugo-Cohen syndrome, we think that this combination of anomalies allows the delineation of a new MCA/MR syndrome, possibly recessively inherited.
92	Waters FM, Lloyd IC, Clayton-Smith J. Apple peel atresia in association with bilateral colobomatous malformation of the optic nerve heads, dysmorphic features, and learning disability - a new syndrome? Ophthalmic Genet 2000 Jun;21(2):117-21	Apple peel atresia of the small bowel is a rare congenital cause of intestinal obstruction. This case report describes a male patient with apple peel atresia and bilateral colobomatous malformation of the optic nerve heads in association with dysmorphic features and learning disabilities. In the absence of a positive family history, we propose that this collection of clinical findings could be due to a new dominant mutation or chromosomal microdeletion.
93	Wheeler CE Jr; Carroll MA; Groben PA; Briggaman RA; Prose NS; Davis DA. Autosomal dominantly inherited generalized basaloid follicular hamartoma syndrome: report of a new disease in a north carolina family. J Am Acad Dermatol 2000 Aug;43 Pt 1(2):189-206	BACKGROUND: An 8-year-old girl presented with hundreds of milia, measuring 1 to 2 mm; comedone-like lesions; skin-colored and hyperpigmented papules on the face, scalp, ears, neck, upper trunk, and lower arms along with diffuse scalp hypotrichosis; and pinpoint palm/sole pits. Onset was in early childhood and the disease was historically present in 6 generations. OBJECTIVE: Our objectives were to delineate the clinical and histopathologic features and mode of inheritance as a base for gene studies. METHODS: Eighteen family subjects were studied. Twenty-six skin biopsy specimens were examined. A detailed pedigree was constructed. A complete literature search was done concerning diseases with generalized basaloid follicular hamartomas. RESULTS: The lesions were basaloid follicular hamartomas and other folliculocentric abnormalities. Inheritance was autosomal dominant. Extensive literature search confirmed the finding of a unique genodermatosis. CONCLUSION: A new genodermatosis termed dominantly inherited generalized basaloid follicular hamartoma syndrome was defined by delineating its clinical and histopathologic features and mode of inheritance and by extensive literature review.
94	Witters I, Moerman P, Fryns JP. Prenatal echographic diagnosis of laryngeal atresia as part of a multiple congenital anomalies (MCA) syndrome. Genet Couns 2000;11(3):215-9	Prenatal echographic diagnosis of laryngeal atresia as part of a multiple congenital anomalies (MCA) syndrome: In this report we present the prenatal second trimester echographic diagnosis of laryngeal atresia in a male fetus with multiple associated congenital anomalies: oesophageal atresia, crossed fused ectopy of the right kidney, mild cutaneous syndactyly of fingers III-V and toes II-III, distinct facial appearance and single umbilical artery. Bilateral voluminous echogenic lungs were the major echographic diagnostic sign. The associated multiple congenital anomalies were not diagnostic for a distinct, recognizable multiple malformation syndrome.
95	Yuksel, Adnan; Seven, M.; Deviren, A.; Cetinel, V.; Ozkilic, A.; Hacihanfioglu, S.; Ulutin, T.; Cenani, A.; Iscan, M.Y. Two female siblings with pre- and postnatal growth retardation, Iris Colobomata, spasticity, facial dysmorphism and dilated ventricles. Eur J Hum Genet 2000, v.8.Supplement 1,	We report two siblings with similar MCA/MR syndrome. Patient 1 showed inadequate growth, neurodevelopmental delay and unusual facial appearence. She was born at term as the first child to healthy parents. No history of prenatal exposure to teratogenic agents was reported. She had presented facial asymmetry, flat occiput, low set and big ears, high forehead, broad nasal bridge, long and thin nose, narrow, high arched palate, hypoplastic mandible and maxilla, esotropia and iris colobomata and sparse eyebrows. Blepharophimosis and ptosis were not evident. Patient 2 resembled her 2 year older older sister. She had broad nasal bridge, long and thin nose, low set and posteriorly angulated ears, large mouth, high palate, micrognathia, iris colobomata, scanty eye-brows, sacral dimple, hypertonicty of limbs, hyperactive deep ten-don reflexes and presence of Babinski sign. On both patients, MRI showed dilated ventricles. Laboratory evaluations showed normal routine blood count, serum chemistry, sweat testing, EEC and karyotype. These new morphological characteritics suggest these siblings may present a new syndrome of genetic disorders.
96	Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, Shapira SK, Farndon PA, Wara DW, Emmal SA, Ferguson BM. A Novel X-Linked Disorder of Immune Deficiency and Hypohidrotic Ectodermal Dysplasia Is Allelic to Incontinentia Pigmenti and Due to Mutations in IKK-gamma (NEMO). Am J Hum Genet 2000 Dec;67(6):1555-1562	Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We have studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected males manifest dysgammaglobulinemia and, despite therapy, have significant morbidity and mortality from recurrent infections. Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. IKK-gamma is required for the activation of the transcription factor known as "nuclear factor kappa B" and plays an important role in T and B cell function. We hypothesize that "milder" mutations at this locus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activators. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is mediated through a tumor necrosis factor/tumor necrosis factor receptor-like signaling pathway, with the IKK signalsome complex playing a significant role.