Genetics
дополнительные статьи

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

06.24.2004

	FIRST PUBLICATIONS 2001 - ABSTRACTS
1	Al-Enesi S, Huber AM, Krafchik BR, Laxer RM. Inflammatory linear verrucous epidermal nevus and arthritis: A new association. J Pediatr 2001;138(4):602-4 Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare, chronic skin condition that begins in early childhood. We present two children with ILVEN and arthritis, a previously undescribed association. We discuss the relevance of this association and suggest appropriate management for this arthritis.
2	Amor DJ, Delatycki MB, Gardner RJMcK, Storey E. Cerebellar ataxia and hypergonadotropic hypogonadism comprise a rare and presumably heterogeneous association. Inheritance in most cases appears to be autosomal recessive, and associated features include deafness, intellectual impairment, and neuropathy. Typically, onset of ataxia is in the first decade and hypogonadism results in primary amenorrhoea in females. We describe two sisters with a previously undescribed pattern of adult onset progressive cerebellar ataxia and secondary amenorrhoea due to hypergonadotropic hypogonadism. Sensorineural deafness with vestibular hypofunction and peripheral sensory impairment were also present, and intellect was normal. Onset of neurological symptoms was in the third decade, with secondary amenorrhoea occurring at the ages of 16 and 32 years, respectively. The association of ataxia and hypergonadotropic hypergonadism has been classified both as a variant of Holmes type ataxia and as a variant of Perrault syndrome, but we suggest the use of a separate category of ataxia with hypergonadotropic hypogonadism.
3	Askmark H, Eeg-Olofsson KE, Johansson A, Nilsson P, Olsson Y, Aquilonius S-M. Parkinsonism and Neck Extensor Myopathy. A New Syndrome or Coincidental Findings? Arch Neurol. 2001;58(2):232-237 Background. Dropped head in parkinsonism has been attributed to dystonia or unbalanced muscle rigidity. To our knowledge, isolated neck extensor myopathy with parkinsonism has been described in only one patient. Objectives. To assess the occurrence of neck extension weakness resulting in dropped head in patients with parkinsonism and to explore whether the head drop might be the consequence of neck extensor myopathy. Patients and Methods. All patients who were evaluated because of parkinsonism in the Department of Neurology in our hospital between January 1, 1997, and December 31, 1999, and were found to have both parkinsonism and neck extension weakness resulting in head drop were studied. The patients underwent clinical examination, blood tests including the levels of creatine kinase and myoglobin and neurophysiological evaluation with needle electromyography and autonomic tests. Open biopsy on a neck muscle was performed in the patients who could cooperate. Results.Of 459 patients evaluated because of parkinsonism, 7 were found to have neck extensor weakness resulting in head drop. Needle electromyography revealed myopathic changes in all 7 patients. Muscle biopsy, which was performed in 5 patients, disclosed myopathic changes in all 5 patients. Electron microscopy revealed mitochondrial abnormalities in 2 of these 7 patients. Three of the patients had concomitant neck rigidity that could contribute to the neck position. All 7 patients had autonomic dysfunction and 6 responded poorly to levodopa therapy, making a diagnosis of multiple system atrophy probable. Conclusion. Parkinsonism may be associated with isolated neck extensor myopathy resulting in dropped head, and this condition should be suggestive of multiple system atrophy.
4	Attia-Sobol J, Encha-Razavi F, Hermier M, Vitrey D, Verloes A, Plauchu H. Lissencephaly type III, stippled epiphyses and loose, thick skin: A new recessively inherited syndrome. Am J Med Genet, 2001;99(1):14-20 We report on two new cases of syndromic lissencephaly in two consanguineous sibs, with skeletal abnormality, born to young, healthy, second cousin parents with healthy children. In Case 1, fetal ultrasound screening at 32 weeks of gestation showed microcephaly, skin infiltration and equinovarus feet. MRI disclosed cerebral agyria, hypoplastic cerebral mantle and posterior agenesis of the corpus callosum. The propositus, a boy, died soon after birth at term. In Case 2, fetal ultrasound study performed at 16 weeks of gestation disclosed skin infiltration. MRI at 22 weeks of gestation showed microcephaly with agenesis of corpus callosum and cerebellar hypoplasia. Pregnancy was terminated at 22 weeks of gestation. The fetus had normal 46, XY karyotype and similar anomalies found in the index case, with cranio-facial edema and arthrogryposis. X-ray films showed epiphyseal stippling of cervical vertebrae, feet and sacrum. Metacarpal bones were shortened with hypoplastic distal phalanges. Neuropathological findings were concordant with the pattern described in type III lissencephaly: an agyric brain with hypoplastic brain stem and cerebellum, severe neuronal loss of the cortical plate, matrix zone, basal ganglia, brainstem nuclei and spinal cord with axonal swelling and microcalcification. This entity seems to be a new syndromic lissencephaly type III, because of epiphyseal calcifications and metacarpophalangeal bone dysplasia.
5	Castriota-Scanderbeg A, Dallapiccola B, Mingarelli R, Kozlowski K. Distinctive metaphyseal chondrodysplasia simulating cartilage hair hypoplasia. Am J Med Genet, 2001; 99(4):289-293 We report on a 5Ѕ year-old Italian girl with a distinctive form of metaphyseal chondrodysplasia simulating cartilage hair hypoplasia. The pattern of metaphyseal changes and the associated bony abnormalities differentiate this patient from all the recognized forms of metaphyseal chondrodysplasia.
6	Chinnery PF, Johnson MA, Walls TJ, Gibson GJ, Fawcett PRW, Jamieson S, Fulthorpe JJ, Cullen M, Hudgson P, Bushby KMD. A novel autosomal dominant distal myopathy with early respiratory failure: Clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci. Ann Neurol 2001; 49(4):443-452 We describe a novel autosomal dominant myopathy presenting in mid-adult life with tibialis anterior weakness. We carried out a detailed clinical assessment of 24 individuals spanning three generations, documenting pathologic features of the muscles in 7 of the 11 affected individuals, including an autopsy study on one case. The second generation of affected individuals presented at an earlier age, and the disease progressed more rapidly than in the first generation. Lung function tests revealed progressive global respiratory muscle weakness detectable from the time of presentation, with preferential diaphragmatic involvement in some cases. Hip girdle and shoulder girdle weakness appeared later in the disease course. We observed a striking correlation between the clinical and pathological features. Clinically unaffected muscles had minimal pathologic change. Fiber splitting, eosinophilic inclusions, and vacuoles with basophilic rims were seen in moderately affected muscles, and fat and fibrous connective tissue replaced muscle fibers in the severely involved muscles. The inclusions were Congophilic and reacted with antibodies to desmin, -amyloid, and phosphorylated tau protein. The disease was not linked to any of the known loci associated with distal myopathies, confirming that the disorder in this family is both genetically and phenotypically distinct.
7	Courville P, Thomine E, Surlemont Y, Hemet J, Metayer J, Lauret P. Epidermal nevus associated with a type I neurofibromatosis and a nephroblastoma: a new epidermal nevus syndrome ? Ann Pathol 2000; 20(6):616-9 We report the case of a 6-year-old boy who showed a large epidermal nevus mixed with a plexiform neurofibroma, which was associated with "cafe au lait" macules and a nephroblastoma. This association could not be classified in one of the five well defined epidermal nevus syndrome. To our knowledge this is the first time that this type of epidermal nevus syndrome has been described, which raises the question of the relationship between neurofibromatosis 1, nephroblastoma and epidermal nevus.
8	de Vries BB, Lees M, Knight SJ, Regan R, Corney D, Flint J, Barnicoat A, Winter RM. Submicroscopic 8pter deletion, mild mental retardation, and behavioral problems caused by a familial t(8;20)(p23;p13). Am J Med Genet 2001;99(4):314-319 Microscopically visible distal 8p deletions have been associated with growth and mental impairment, minor facial anomalies, congenital heart defects, and behavioral problems. We report two cousins with mild retardation and behavioral problems, including inappropriate sexual behavior and pyromania. Familial learning difficulties on the grandfather's side incompatible with Mendelian inheritance prompted telomere screening, which detected a submicroscopic terminal 8p deletion of < 5.1 Mb. The cousins' mothers both carried a t(8;20)(p23;p13) balanced translocation. The frequently observed microcephaly in patients with microscopically visible deletions of 8pter is lacking in both cousins, suggesting that the gene(s) causing the microcephaly is centromeric to the deleted region. The absence of cardiac defects in the cousins confirms the more proximal location of gene(s) causing these abnormalities in other reported cases with microscopically visible 8pter deletions and supports involvement of the GATA4 gene. Moreover, the current cases predict the presence of a putative gene(s) involved in behavior in the most telomeric 5.1 Mb of the p-arm of chromosome 8. This first clinical report of a submicroscopic subtelomeric 8p deletion gives more insight into the so-called 8p- syndrome and demonstrates the difficulty in making a clinical diagnosis for a submicroscopic 8pter deletion in an individual patient with mental retardation.
9	Delb W, Lipfert S, Henn W. Mandibulofacial dysostosis, microcephaly and thorax deformities in two brothers: a new recessive syndrome? Clin Dysmorphol 2001; 10(2):105-119 We report two brothers who presented with mandibulofacial dysostosis, growth retardation, microcephaly, thoracic deformities and conductive hearing loss along with asplenia in one case and aplasia of the gallbladder in the other. The pattern of malformations differs significantly from established syndromes with mandibulofacial dysostosis such as Nager syndrome or Genee-Wiedemann syndrome and also from cerebro-costo-mandibular syndrome. As chromosome analysis revealed normal male karyotypes, we consider this to be a distinct heritable syndrome that may be either autosomal recessive or X-chromosomal recessive.
10	Der Kaloustian VM, Pelletier M, Costa T, Blackston DR, Oudjhane K. A new syndrome with craniofacial and skeletal dysmorphisms and developmental delay. Clin Dysmorphol 2001;10(2):87-93 We report a 16-year-old boy with multiple craniofacial and skeletal dysmorphic features including brachycephaly, acrocephaly, hypertelorism, wide palpebral fissures, broad nose, anteverted nares, broad columella, long and smooth philtrum, thin upper lip, macrostomia, carp-like mouth, micrognathia, low-set and posteriorly angulated ears with small and abnormal pinnae, a low posterior hairline, a short neck, hypoplastic and widely-spaced nipples, multiple severe pterygia, an umbilical hernia, metatarsus varus, low implantation of the halluces, and delayed motor and language development. An MRI of the head showed bilateral frontal pachygyria but no sign of heterotopia. The unique features of our patient suggest that he represents a new syndrome.
11	Fatinni Y, Asindi A, Al Falki Y, Al Harthi A, Al Fifi S, Al-Daama S. Possible new autosomal recessive syndrome of congenital lymphoedema, nail dystrophy and esotropia in a Saudi family. Acta Paediatr 2001;90(2):151-3 This paper presents a family case of two brothers and two sisters with congenital lower limb lymphoedema, nail dystrophy, and with esotropia in two of them. They are offspring of healthy parents who are first cousins. This combination of congenital lymphoedema, nail dystrophy and esotropia in this sibship differs from other reported cases of congenital lymphoedema and most likely constitutes a previously unrecognized autosomal recessive syndrome.
12	Fernandez M, Raskind W, Wolff J, Matsushita M, Yuen E, Graf W, Lipe H, Bird T. Familial dyskinesia and facial myokymia (FDFM): A novel movement disorder. Ann Neurol 2001;49(4):486-492 We describe here familial dyskinesia and facial myokymia (FDFM), a novel autosomal dominant disorder characterized by adventitious movements that sometimes appear choreiform and that are associated with perioral and periorbital myokymia. We report a 5-generation family with 18 affected members (10 males and 8 females) with FDFM. The disorder has an early childhood or adolescent onset. The involuntary movements are paroxysmal at early ages, increase in frequency and severity, and may become constant in the third decade. Thereafter, there is no further deterioration, and there may even be improvement in old age. The adventitious movements are worsened by anxiety but not by voluntary movement, startle, caffeine, or alcohol. The disease is socially disabling, but there is no intellectual impairment or decrease in lifespan. A candidate gene and haplotype analysis was performed in 9 affected and 3 unaffected members from 3 generations of this family using primers for polymorphic loci closely flanking or within genes of interest. We excluded linkage to 11 regions containing genes associated with chorea and myokymia: 1) the Huntington disease gene on chromosome 4p; 2) the paroxysmal dystonic choreoathetosis gene at 2q34; 3) the dentatorubral-pallidoluysian atrophy gene at 12p13; 4) the choreoathetosis/spasticity disease locus on 1p that lies in a region containing a cluster of potassium (K+) channel genes; 5) the episodic ataxia type 1 (EA1) locus on 12p that contains the KCNA1 gene and two other voltage-gated K+ channel genes, KCNA5 and KCNA6; 6) the chorea-acanthocytosis locus on 9q21; 7) the Huntington-like syndrome on 20p; 8) the paroxysmal kinesigenic dyskinesia locus on 16p11.2-q11.2; 9) the benign hereditary chorea locus on 14q; 10) the SCA type 5 locus on chromosome 11; and 11) the chromosome 19 region that contains several ion channels and the CACNA1A gene, a brain-specific P/Q-type calcium channel gene associated with ataxia and hemiplegic migraine. Our results provide further evidence of genetic heterogeneity in autosomal dominant movement disorders and suggest that a novel gene underlies this new condition.
13	Guschmann M, Horn D, Entezami M, Urban M, Hänel S, Kunze J, Vogel M. Mesomelic campomelia, polydactyly and Dandy-Walker cyst in siblings. Prenatal Diagnosis 2001; 21(5):378-382 The present report describes two fetuses, one female and one male, with thus far undescribed skeletal malformations. The mother was a gravida 2, para 0. Both pregnancies were terminated in the second trimester because of multiple congenital anomalies diagnosed ultrasonographically resembling a short rib-polydactyly syndrome. Both fetuses were found to have postaxial hexadactyly of the hands and feet, marked bilateral campomelia of the forearm and shank bones, and a Dandy-Walker cyst. In addition, the fourth ventricle was dilated in the first sibling and the second sibling had an inverse intestinal malrotation. A literature search failed to reveal similar observations.
14	Hadziselimovic F; Fliegel CH; Miny P. A novel syndrome involving primary skeletal growth and retardation in siblings.Clin Dysmorphol 2001;10(1):33-6 An identical pattern of malformations was found in two brothers both having microcephaly and severe developmental delay. Additionally, they had hypotelorism, epicanthic folds, and convergent strabismus. There was shortening of either the radius or the tibia and shortening of the first metacarpals. Persistently dorsally flexed fingers and toes were noted, all of which are unusually long. Both boys had a high-pitched voice and were unable to communicate verbally at the age of 4.5 years. They both developed short stature. One brother has anal atresia; the other had a pulmonary artery atresia, VSD, ASD, and an over-riding aorta. This apparently new syndrome is possibly an autosomal, or a X-linked recessive trait.
15	Hisama FM, Zemel S, Cherniske EM, Vladutiu GD, Pober BR. 46,XX gonadal dysgenesis, short stature, and recurrent metabolic acidosis in two sisters. Am J Med Genet 2001;98(2):121-124 Gonadal (ovarian) dysgenesis in 46,XX individuals is genetically heterogeneous. We report on two sisters who, in addition to primary ovarian failure, have marked short stature and recurrent episodes of dehydration with metabolic acidosis. Studies performed during one of these episodes suggested mitochondrial dysfunction; however, results of biochemical analysis of electron transport chain activity in skeletal muscle and mitochondrial DNA studies were normal. We discuss the phenotype in relation to previously described conditions of 46,XX gonadal dysgenesis. We suggest this constellation of findings represents a new syndrome.
16	Hoffman HM, Bastian JF, Bird LM. Humoral immunodeficiency with facial dysmorphology and limb anomalies: a new syndrome. Clin Dysmorphol 2001;10(1):1-8 We report a 6 year old girl with an isolated humoral immune deficiency and a unique combination of dysmorphic features. Physical findings include microcephaly, micrognathia, sickle shaped eyebrows, hypoplastic alae nasi, thenar hypoplasia, partial 4-5 syndactyly of toes, recessed great toes, anterior anus, and hypoplastic labia minora. Radiographic findings include triphalangeal thumbs and hypoplastic first metatarsals. She has postnatal growth retardation and her development is substantially slower than her twin's. Her clinical course has been complicated by recurrent sinopulmonary infections and pneumococcal bacteraemia. Laboratory evaluation revealed hypogammaglobulinaemia, absent B cells, and a 46,XX karyotype. A review of the literature and the London Dysmorphology Database did not produce any recognizable syndromes that match her constellation of findings. She may represent a unique syndrome of unknown etiology.
17	Inui K, Yanagihara K, Otani K, Suzuki Y, Akagi M, Nakayama M, Ida H, Okada S. A new variant neuropathic type of Gaucher’s disease characterized by hydrocephalus, corneal opacities, deformed toes, and fibrous thickening of spleen and liver capsules. J Pediatr 2001;138(1):137-139 We report a new variant type of Gaucher’s disease characterized by hydrocephalus, corneal opacities, deformed toes, gastroesophageal reflux, and fibrous thickening of splenic and hepatic capsules. This patient had 1 D409H allele. He differed from other reported cases with a 1342G to C (D409H) homozygous mutation (onset at 4 months, no cardiac involvement until the age of 12 years, and massive hepatosplenomegaly with fibrous thickening of spleen and liver capsules). Enzyme replacement therapy was given for 4 years, resulting in an improvement of visceral and hematologic abnormalities but no neurologic improvement.
18	Kantaputra PN, Eiumtrakul P, Matin T, Opastirakul S, Visrutaratna P, Mevate U. Cryptophthalmos, dental and oral abnormalities, and brachymesophalangy of second toes: New syndrome or Fraser syndrome? Am J Med Gene 2001;98(3):263-268 We report on an 8-year-old Thai girl with bilateral complete cryptophthalmos, facial asymmetry, delayed bone age, brachymesophalangy and medial deviation of the second toes, and dental anomalies. The dental anomalies consist of delayed dental development, congenital absence of the second premolars, microdontia of the deciduous molars. A fibrous band of the buccal mucosa was found. Dental anomalies are rare among patients with Fraser syndrome. They have not been reported in either isolated or other syndromic cryptophthalmos. The oral manifestations and brachymesophalangy of the second toes found in our patient may represent newly recognized findings associated with cryptophthalmos or they may represent a newly recognized syndrome.
19	Kozlowski K, Posen S. Malignant hypophosphathaemic bone disease. Eur J Radiol 2001;37(2):134-138 A case of crippling osteoporosis with muscular weakness, hypophosphatemia, hyperparathyroidism, defective skeletal calcification and cartilage destruction is reported. The patient, a male was observed from the age of 212 until his death at the age of 33 years. This bone/cartilage disease failed to respond to phosphate supplementation, parathyroidectomy and calcitriol. We believe this may represent a hitherto undescribed entity.
20	Kuzuhara S, Kokubo Y, Sasaki R, Narita Y, Yabana T, Hasegawa M, Iwatsubo T. Familial amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Kii peninsula of Japan: Clinical and neuropathological study and tau analysis. Ann Neurol 2001;49(4):501-511 We report the first case of neuropathologically verified parkinsonism-dementia complex of the Kii peninsula, together with the patient's brother, who had amyotrophic lateral sclerosis. The propositus woman developed parkinsonism and dementia at 63 years of age and died at 70 without displaying clinical features of amyotrophic lateral sclerosis. The brain exhibited marked atrophy of the frontal and temporal lobes. Microscopically, there were many neurofibrillary tangles in the central nervous system, most markedly in the mesial temporal lobe and deep nuclei, as well as changes of amyotrophic lateral sclerosis but no senile plaques or Lewy bodies. Neurofibrillary tangles exhibited twisted tubule structures on electon microscopic examination, and an analysis of insoluble tau protein extracted from the fresh brain revealed a 60-, 64-, 68-kD triplet. The tau gene exhibited no mutations. Her brother developed progressive bulbar palsy-type amyotrophic lateral sclerosis at 45 years of age and died at 49 without presenting with dementia or parkinsonism. Neuropathological examination revealed not only pathologic features of amyotrophic lateral sclerosis but also a moderate number of neurofibrillary tangles in the temporal cortex and deep nuclei. The siblings were neuropathologically similar despite their different clinical manifestations. These findings suggest that amyotrophic lateral sclerosis and parkinsonism-dementia complex of this family may be phenotypic variants of a tauopathy caused by genetic abnormalities.
21	LaDine BJ, Simmons JA, Shrimpton AE, Hoo JJ. Syndrome of short stature, widow's peak, ptosis, posteriorly angulated ears, and joint problems: Exclusion of the Aarskog (FGD1) gene as a candidate gene. Am J Med Genet 2001;99(3):248-251 A syndrome encompassing postnatal onset of short stature, widow's peak, ptosis, posteriorly angulated ears, and limitation of forearm supination is reported in a boy and his mother. The boy has not yet experienced dislocation of patella or other joint anomaly except for limitation of supination of the forearms. On the other hand, the mother has a milder limitation of supination only on the left arm and is devoid of ptosis. Their condition is reminiscent of that described in the family reported by Kapur et al. [[1989]: Am. J. Med. Genet. 33: 357-363.], which showed an X-linked dominant mode of inheritance. DNA study on our family using an intragenic polymorphism of the Aarskog syndrome (FGD1) gene and four other adjacent markers convincingly excludes the possibility that their condition could be caused by a mutation of the FGD1 gene. Our family and the family reported by Kapur et al. may suggest segregation of a novel X-linked dominant condition.
22	Lammer EJ, Scholes T, Abrams L. Autosomal recessive tetralogy of fallot, unusual facies, communicating hydrocephalus, and delayed language development: a new syndrome? Clin Dysmorphol 2001;10(1):9-13 We report a pattern of malformation affecting five of seven siblings born to unaffected Afghani parents who are first cousins. Their first two children died during infancy of cyanotic congenital heart defects. Two living male siblings have tetralogy of Fallot, developmental delay principally affecting language skills, and short palpebral fissures or midfacial hypoplasia. Another male has communicating hydrocephalus and hypertelorism. The striking number of siblings with tetralogy of Fallot, or another cyanotic congenital heart defect, and the parental consanguinity, suggests autosomal recessive inheritance in this family. While several other families have been identified with apparent recessive inheritance of tetralogy of Fallot, the associated malformations in our family suggest a unique, and previously unreported, malformation pattern.
23	Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltone LA. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci (USA) 2001; 98(6):3387-3392 Herein we report the clinical, histopathological, and molecular features of a cancer syndrome with predisposition to uterine leiomyomas and papillary renal cell carcinoma. The studied kindred included 11 family members with uterine leiomyomas and two with uterine leiomyosarcoma. Seven individuals had a history of cutaneous nodules, two of which were confirmed to be cutaneous leiomyomatosis. The four kidney cancer cases occurred in young (33- to 48-year-old) females and displayed a unique natural history. All these kidney cancers displayed a distinct papillary histology and presented as unilateral solitary lesions that had metastasized at the time of diagnosis. Genetic-marker analysis mapped the predisposition gene to chromosome 1q. Losses of the normal chromosome 1q were observed in tumors that had occurred in the kindred, including a uterine leiomyoma. Moreover, the observed histological features were used as a tool to diagnose a second kindred displaying the phenotype. We have shown that predisposition to uterine leiomyomas and papillary renal cell cancer can be inherited dominantly through the hereditary leiomyomatosis and renal cell cancer (HLRCC) gene. The HLRCC gene maps to chromosome 1q and is likely to be a tumor suppressor. Clinical, histopathological, and molecular tools are now available for accurate detection and diagnosis of this cancer syndrome.
24	Lemire EG, Stoeber GP, Anselmo M, Lowry RB. Two brothers with severe developmental delay, growth retardation and unusual appearance. Clin Dysmorphol 2001;10(2):111-114 We report on two brothers with short stature, severe developmental delay and unusual appearance. Several conditions including the Russell-Silver, Dubowitz, Floating-Harbour and Cockayne syndromes were considered in the differential diagnosis, but subsequently rejected. These two cases are likely to represent a new autosomal recessive or X-linked recessive syndrome.
25	Lev D, Watemberg N, Aviram A, Fishoff J, Antman E, Lerman-Sagie T. Febrile convulsions, ataxia, developmental delay, and obesity: a new syndrome? J Child Neurol 2001;16(3):174-176 We describe the association of recurrent complicated febrile convulsions, developmental delay, ataxia, and obesity in three unrelated girls. The three girls, aged 3 to 4 years, were all born to healthy, nonconsanguineous parents and have normal siblings. Their birth weight was appropriate for gestational age. They are not dysmorphic and have normal head circumference. Development is delayed; they all walked with an ataxic gait after the age of 2 years and started speaking at 3 years. Their growth charts are remarkably alike: they initially had a normal growth curve and around 24 months of age started to gain weight excessively. They all continue to suffer from complicated febrile seizures, which started before 12 months of age, and are resistant to prophylactic anticonvulsants. Metabolic evaluation is normal. They have normal magnetic resonance images and electroencephalograms. Fragile X and Prader-Willi syndromes were ruled out. We suggest that this is a new mental retardation syndrome that should be considered in children with recurrent febrile convulsions, developmental delay, and obesity. In a recent study, mutations in the beta4 calcium channel were identified in the mutant epileptic mouse that presents with epilepsy, mental retardation, and ataxia. We hypothesize that a calcium channel gene may be involved in this syndrome.
26	Levy-Lahad E, Wildin RS. Neonatal diabetes mellitus, enteropathy, thrombocytopenia, and endocrinopathy: Further evidence for an X-linked lethal syndrome. J Pediatr 2001;138(4):577-580 We describe an unusual family with a fatal genetic syndrome of neonatal diabetes mellitus (DM), enteropathy, endocrinopathy, and severe infections with variable thrombocytopenia. All affected individuals are male; X-linked inheritance is likely. The most common clinical features are neonatal DM, inanition, and enteropathy; a variety of other autoimmune phenomena are less frequent. Clinical variability within and among families is common, including lack of one or more cardinal features. The syndrome is usually fatal, but survival is sometimes possible with immunosuppressive therapy. Clinical variability and frequent new mutations may contribute to poor recognition and underreporting of similar cases.
27	Lin JC, Borregaard N, Liebman HA, Carmel R. Deficiency of the specific granule proteins, R-binder/transcobalamin I and lactoferrin, in plasma and saliva: A new disorder. Am J Med Genet 2001;100(2):145-151 The mechanisms of hereditary deficiency of R binder, which originates in neutrophils and exocrine gland epithelium, are unknown and may be multiple. This led us to examine if defective R binder synthesis also involves proteins that colocalize with it in neutrophil-specific granules and exocrine epithelial cells and may be under common regulatory control. Stored plasma and saliva samples from five unrelated R binder-deficient patients and control subjects were assayed for R binder, lactoferrin, cationic antimicrobial protein-18, neutrophil gelatinase-associated lipocalin, gelatinase, lysozyme, and myeloperoxidase. One patient, patient A, had lactoferrin levels below the limits of detection in both plasma and saliva in addition to his R binder deficiency. Although his deficiency involved lactoferrin as well, he had no history of predisposition to infection. PCR amplification of his R binder gene promoter region and the beginning of the first exon revealed no DNA abnormalities. His son and the son of his equally deficient brother, both presumptive heterozygotes, had mild deficiency of both R binder and lactoferrin. The results show that R binder deficiency exists in at least two forms. One, presumably the less common of the two forms, is the new hereditary entity described here, which is characterized by deficiency of more than one specific granule protein in both plasma and saliva. Despite this more widely distributed absence of the proteins than is found in congenital specific granule deficiency, infection posed no clinical problem in the affected patient.
28	Megarbane A. A new familial syndrome with facial abnormalities, abnormal EEG, and mental retardation. Clin Dysmorphol 2001;10(2):129-133 Two sisters are reported with up-slanting palpebral fissures, hypertelorism, ptosis, a broad, bifid nasal tip, a high-arched palate, mental retardation, abnormal EEG and hand malformations in one of the patients. The girls' parents originate from the same village. Although the findings resemble the recently defined neurofaciodigitorenal syndrome, some findings suggest that this is a newly recognized syndrome.
29	Mégarbané A, Waked N, Chouery E, Moglabey YB, Saliba N, Mornet E, Serre J-L, Slim R. Microcephaly, cutis verticis gyrata of the scalp, retinitis pigmentosa, cataracts, sensorineural deafness, and mental retardation in two brothers. Am J Med Genet 2001;98(3):244-249 We describe the cases of two brothers with microcephaly, primary cutis verticis gyrata of the scalp, prominent supraorbital ridges, large nose, hypertelorism, exotropia, progressive retinitis pigmentosa, cataracts, sensorineural hearing loss, kyphoscoliosis, and mental retardation. A review of the literature focusing on the major clinical findings suggests that our cases may represent a hitherto unreported new syndrome.
30	Morimoto J, Kaneoka H, Murata T, Sato YN, Ogahara S, Hirose S, Naito S, Naritomi K. Proximal symphalangism with coarse facial appearance, mixed hearing loss, and chronic renal failure: New malformation syndrome? Am J Med Genet 2001; 98(3):269-272 A 25-year-old man is described with short stature, moderate mental retardation, an abnormal facial appearance, a webbed neck, skeletal abnormalities including proximal symphalangism of bilateral second through fifth fingers, mixed hearing loss, and slowly progressive, sclerosing nephropathy. He was large at birth with generalized edema, more pronounced around the jaw, neck and the upper part of the body, but became short with increasing age, and currently measures 143 cm (-4.9 SD). He had intermittent proteinuria and slowly progressive deterioration of the renal function. A biopsy of the left kidney showed global glomerular sclerosis with interstitial fibrosis. He was placed on maintenance peritoneal dialysis at age 17 years, and now on hemodialysis. His skeletal abnormalities included, in addition to proximal symphalangism, stenosis of the cervical canal, scoliosis, brachydactyly of the hands, hypoplastic hip joints, and pes valgus. Other abnormalities noted were a communicating defects of the diaphragm (surgically corrected), bilateral inguinal hernia and cryptorchidism. These clinical manifestations indicate a hitherto undescribed combination of manifestations and nephropathy.
31	Schelhaas HJ, Ippel PF, Hageman G, Sinke RG, van der Laan EN, Beemer FA. Clinical and genetic analysis of a four-generation family with a distinct autosomal dominant cerebellar ataxia. Journal of Neurology, 2001; 248(2):113-120 The autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of neurodegenerative disorders characterised by progressive cerebellar dysfunction in combination with a variety of other associative features. Since 1993 ADCAs have been increasingly characterised in terms of their genetic mutation and are referred to as spinocerebellar ataxias (SCAs). Some families with ADCA cannot be assigned to any of the known genotypes, which implies further genetic heterogeneity. We investigated the clinical symptoms of 12 patients of a four-generation family with ADCA and carried out mutation and genetic linkage studies. The family showed a relatively mild cerebellar ataxic syndrome with congitive impairment, poor performance on the Wisconsin Card Sorting Test, myoclonus, and a postural irregular tremor of slow frequency. Age at disease onset and severity of cerebellar signs and symptoms suggest anticipation. The genetic loci implicated in ADCA were excluded by mutation analyses (SCA 1,2,3,6,7,8,12) and genetic linkage (SCA 4,5,6,10,11). We conclude that this family represents a clinically and genetically distinct form of SCA.
32	Schmidt H; Rudolph G; Hergersberg M; Schneider K; Moradi S; Meitinger T. Retinal detachment and cataract, facial dysmorphism, generalized osteoporosis, immobile spine and platyspondyly in a consanguinous kindred - a possible new syndrome. Clin Genet 2001; 59(2):99-105 We report on a consanguineous family with 6 children (out of 7) affected by a spondylo-ocular syndrome. Clinical features include cataract, loss of vision due to retinal detachment, facial dysmorphism, facial hypotonia, normal height with disproportional short trunk, immobile spine with thorakal kyphosis and reduced lumbal lordosis. On ophthalmological examination of the index patient, a dense cataract and complete retinal detachment could be detected on the right eye. On the left eye, an absent lens nucleus was found, but no retinal detachment. On radiological examination, there was generalized moderate osteoporosis; the spine showed marked platyspondyly and the bone age was advanced. On laboratory investigations, a normal excretion of amino acids, mucopolysaccharides and oligosaccharides could be found. The phenotypical spectrum observed in the 6 affected individuals was rather uniform. The karyotype was normal in all affected children. This hitherto undescribed combination of oculo-skeletal symptoms shows most resemblance with connective tissue disorders, suggesting a range of candidate genes for mutation analysis.
33	Semerci CN, Bebitoglu I, Kacar A, Yurttagul S, Ercakmak S, Ertoy D, Ozaltin F, Balci S. An unusual fetus with complete absence of thoracic, lumbar and sacral vertebrae, bilateral renal agenesis, VSD, meningomyelocele, imperforate anus, and teratoma. Clin Dysmorphol 2001;10(1):57-60 We present a 30 week old male fetus who had a very interesting malformation complex which can not be explained by teratogenic or hereditary diseases. The aim of this paper is to discuss this complicated entity and compare it with other reported cases.
34	Teebi AS; Druker HA. Brachycephaly, cutis aplasia congenita, blue sclerae, hypertelorism, polydactyly, hypoplastic nipples, failure to thrive, and developmental delay: a distinct autosomal recessive syndrome? Clin Dysmorphol 2001;10(1):69-70 We report a 6-year-old male of first cousin parents with the unique constellation of frontal bossing with brachycephaly, cutis aplasia congenita, blue sclerae, hypertelorism, hypoplastic nipples, rudimentary unilateral post-axial polydactyly of the hand, failure to thrive, mild to moderate developmental delay and sociable personality. Knoblock-Layer syndrome and Smith-Lemli-Opitz syndrome were considered in the differential diagnosis and were excluded. No similar cases were found in LDDB or other databases.
35	Tuysuz B; Beker BD; Centel T; Ungur S; Iter O. Unilateral tibial agenesia with preaxial polysyndactyly and renal disorder in two patients: a new syndrome? Clin Dysmorphol 2001;10(1):37-40 Left tibial agenesis, polysyndactyly with talipes equinovarus deformity and Grade IV vesicoureteral reflux of the right kidney are described in a 40-day-old male and an unrelated 1-month-old male, is also reported with right tibial agenesis, polysyndactyly with talipes equinovarus deformity and right kidney agenesis and left Grade V vesicoureteral reflux. No other pathology was recorded. Follow up at 1 year and 3 years, respectively, revealed normal motor and mental development. As this combination has been unpublished before, we believe that this a new syndrome.
36	Verhoeven NM, Jojanneke H. J. Huck JHJ, Roos B, Struys EA, Salomons GS, Douwes AC, van der Knaap MS, Jakobs C. Transaldolase Deficiency: Liver Cirrhosis Associated with a New Inborn Error in the Pentose Phosphate Pathway. Am J Hum Genet 2001; 68:1086-1092 This article describes the first patient with a deficiency of transaldolase (TALDO1 [E.C.2.2.1.2]). Clinically, the patient presented with liver cirrhosis and hepatosplenomegaly during early infancy. In urine and plasma, elevated concentrations of ribitol, D-arabitol, and erythritol were found. By incubating the patient's lymphoblasts and erythrocytes with ribose-5-phosphate and subsequently analyzing phosphate sugar metabolites, we discovered a deficiency of transaldolase. Sequence analysis of the transaldolase gene from this patient showed a homozygous deletion of 3 bp. This deletion results in absence of serine at position 171 of the transaldolase protein. This amino acid is invariable between species and is located in a conserved region, indicating its importance for enzyme activity. The detection of this new inborn error of pentose metabolism has implications for the diagnostic workup of liver problems of unknown etiology.
37	Verloes A; Lesenfants S. New syndrome: clavicle hypoplasia, facial dysmorphism, severe myopia, single central incisor and peripheral neuropathy. Clin Dysmorphol 2001;10(1):29-31 A new syndrome of unknown origin is reported, consisting of facial dysmorphism (upward slanted palpebral fissures, single superior central incisor, narrow, cylindrical nose with hypoplastic alae), bilateral agenesis of the clavicles, limited movements of elbow and fingers, calf atrophy and pes cavus with abolished reflexes (Charcot-Marie-Tooth syndrome, unspecified type).