Update on a family with hand-foot-genital syndrome: hypospadias and urinary tract abnormalities in two boys from the fourth generation.

We describe a fourth generation of involvement with hand-foot-genital syndrome. The first 3 generations of this family, which included 5 affected females and no affected males, were reported previously by Verp et al. [1983]. In the fourth generation, 2 affected males are identified. To our knowledge, the findings of bilateral vesicoureteral reflux in one boy and bilateral ureteropelvic junction obstruction in his cousin represent the first reports of urinary tract abnormalities in males with this syndrome.     

Autosomal dominant preaxial deficiency,postaxial polydactyly,and hypospadias

We report on 3 individuals, a man and his son and daughter, who were born with prexial dificiencies of the hands and feet and postaxial polydactyly of the hands. Both males also had glandular hypospadias. Certain of these findings resemble those found in the hand-foot-genital syndrome; however, we conclude that this family has a hitherto unreported by a single gene defect of preaxial deficiencies and postaxial polydactyly in the same individual is of note. © 1993 Wiley-Liss, Inc.     

Barth syndrome: Clinical features and confirmation of gene localisation to distal Xq28

Barth syndrome is an X-linked disorder characterised by cardioskeletal myopathy of variable severity usually fatal in childhood, and neutropenia. We ascertained a large pedigree with affected males in 3 generations. All affected males had dilated cardiomyopathy, with endocardial fibroelastosis (EFE) in some. The locus for Barth syndrome in this family was found to be closely linked to DXS52 (z = 2.78, θ = 0.0). The family was non-recombinant for DXS52 in distal Xq28, but recombinant for DXS374 which maps proximal to DXS52. This localised Barth syndrome distal to DXS374, confirming a previous localisation to distal Xq28. As yet there is no evidence for genetic heterogeneity of Barth syndrome. © 1993 Wiley-Liss, Inc.     

Cowden syndrome: report of a large family with macrocephaly and increased severity of signs in subsequent generations

Hanssen AMN, Werquin H, Suys E, Fryns JP. Cowden syndrome: report of a large family with macrocephaly and increased severity of signs in subsequent generations.
Clin Genet 1993: 44: 281–286. © Munksgaard, 1993
We report Cowden syndrome in a large four-generation family, paying special attention to the apparently greater severity and earlier onset of signs and symptoms in subsequent generations. Macrocephaly was present in all affected individuals and was markedly progressive in three of six affected children of the fourth generation, and associated with slight to moderate delay in psychomotor development.     

Applicability of a checklist for clinical screening of the fragile X syndrome

In a population of 340000 in Southern Häme, Finland, there were 541 intellectually disabled adult males (> 16 years) known to the District Organisation for the Care of the Mentally Retarded in August 1993. Of these, 197 already had a confirmed etiological diagnosis, with 20 having the fragile X syndrome. The other 344 males were screened for the fragile X syndrome using a three-step method: a clinical checklist used by a specialist nurse, a clinical examination by a physician who was very familiar with the fragile X syndrome, and the FRAXA-locus gene test. Six new fragile X males were found. The minimum prevalence of the fragile X syndrome in the district was calculated to be 1:4400.     

A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome

Guttmacher syndrome, a dominantly inherited combination of distal limb and genital tract abnormalities, has several features in common with hand-foot-genital syndrome (HFGS), including hypoplastic first digits and hypospadias. The presence of features not seen in HFGS, however, including postaxial polydactyly of the hands and uniphalangeal 2(nd) toes with absent nails, suggests that it represents a distinct entity. HFGS is caused by mutations in the HOXA13 gene. We have therefore re-investigated the original Guttmacher syndrome family, and have found that affected individuals are heterozygous for a novel missense mutation in the HOXA13 homeobox (c.1112A>T; homeodomain residue Q50L), which arose on an allele already carrying a novel 2-bp deletion (-78-79delGC) in the gene's highly conserved promoter region. This deletion produces no detectable abnormalities on its own, but may contribute to the phenotype in the affected individuals. The missense mutation, which alters a key residue in the recognition helix of the homeodomain, is likely to perturb HOXA13's DNA-binding properties, resulting in both a loss and a specific gain of function.     

Screen for MAOA mutations in target human groups

Brunner et al. [1993: Am J Hum Genet 52: 1032-1039; 1993: Science 262:578-580] described males with an MAO-A deficiency state resulting from a premature stop codon in the coding region of the MAOA gene. This deficiency state was associated with abnormal levels of amines and amine metabolites in urine and plasma of affected males, as well as low normal intelligence and apparent difficulty in impulse control, including inappropriate sexual behavior. In the present study, disruption of the MAOA gene was evaluated in males with mental retardation with and without a history of sexually deviant behavior, as well as normal controls, healthy males, and patients with other diseases (Parkinson disease, Lesch-Nyhan syndrome). When available, plasma samples were evaluated first for levels of 3-methoxy, 4-hydroxyphenolglycol (MHPG), a metabolite of norepinephrine which serves as the most sensitive index of MAO-A activity in humans. Blood DNA from individuals with abnormally low MHPG, and from other individuals for whom metabolite levels were not available, were screened for nucleotide variations in the coding region of the MAOA gene by single-strand conformational polymorphism (SSCP) analysis across all 15 exons and splice junctions, and by sequencing, when indicated by either altered metabolites or SSCP shifts. No evidence for mutations disrupting the MAOA gene was found in 398 samples from the target populations, including institutionalized mentally retarded males (N = 352) and males participating in a sexual disorders clinic (N = 46), as well as control groups (N = 75). These studies indicate that MAOA deficiency states are not common in humans.     

Simpson-Golabi-Behmel syndrome: Congenital diaphragmatic hernia and radiologic findings in two patients and follow-up of a previously reported case

This report suggests the association of congenital diaphragmatic hernia in Simpson-Golabi-Behmel syndrome by describing two unrelated males with this malformation. One male was the maternal half-nephew of our previously reported 8-year-old boy with this syndrome. Review of the skeletal roentgenograms of these 2 affected males, and those of the previously reported 8-year-old, documents flare of the iliac wings, narrow sacroiliac notches, and the presence of two carpal ossification centers as a newborn (“advanced bone age”). We also report the follow-up of the 8-year-old boy, now 16 years old, who continues to have significant overgrowth and speech, dental, developmental, and adjustment problems. © 1993 Wiley-Liss, Inc.     

Twins and their mildly affected mother with Weaver syndrome

Dumić M, Vuković J, Cvitković M, Medica I. Twins and their mildly affected mother with Weaver syndrome. Clin Genet 1993: 44: 338–340. © Munksgaard, 1993
A pair of twins, a brother and sister, with the complete form of Weaver syndrome (overgrowth, macrocephaly, facial, skeletal, nail and feet anomalies) and their mildly affected mother are reported, suggesting autosomal dominant inheritance. They all have plantar and palmar hyper-hydrosis and twins also have nail dysplasia, symptoms which have not yet been described in this syndrome.     

Anthropometric and craniofacial patterns in mentally retarded males with emphasis on the fragile X syndrome

Butler MG, Pratesi R, Watson MS, Breg WR, Singh DN. Anthropometric and craniofacial patterns in mentally retarded males with emphasis on the fragile X syndrome. Clin Genet 1993: 44: 129–138. © Munksgaard, 1993 Anthropometric and craniofacial profile patterns indicating the percent difference from the overall mean were developed on 34 physical parameters with 31 white, mentally retarded males (23 adults and 8 children) with the fra(X) syndrome matched for age with 31 white, mentally retarded males without a known cause of their retardation. The fra(X) syndrome males consistently showed larger dimensions for all anthropometric variables, with significant differences for height, sitting height, arm span, hand length, middle finger length, hand breadth, foot length, foot breadth, and testicular volume. A craniofacial pattern did emerge between the two groups of mentally retarded males, but with overlap of several variables. Significant differences were noted for head circumference, head breadth, lower face height, bizygomatic diameter, inner canthal distance, ear length and ear width, with the fra(X) syndrome males having larger head dimensions (head circumference, head breadth, head length, face height and lower face height), but smaller measurements for minimal frontal diameter, bizygomatic diameter, bigonial diameter, and inner canthal distance. Several significant correlations were found with the variables for both mentally retarded males with and without the fra(X) syndrome. In a combined anthropometric and craniofacial profile of 19 variables comparing 26 white fra(X) syndrome males (13 with high expression (>30%) and 13 with low expression (<30%), but matched for age), a relatively flat profile was observed with no significant differences for any of the variables. Generally, fra(X) syndrome males with increased fragile X chromosome expression have larger amplifications of the CGG trinucleotide repeat of the FMR-1 gene. No physical differences were detectable in our study between fra(X) males with high expression and apparently larger amplifications of the CGG trinucleotide repeats compared with those patients with low expression. Our research illustrates the use of anthropometry in identifying differences between mentally retarded males with or without the fra(X) syndrome and offers a comprehensive approach for screening males for the fra(X) syndrome and selecting those individuals for cytogenetic and/or molecular genetic testing.     

Linkage analysis-in a family with complete type congenital stationary night blindness with and without myopia

Dry KL, Van Dorp DB, Aldred MA, Brown J, Hardwick LJ, Wright AF. Linkage analysis in a family with complete type congenital stationary night blindness with and without myopia.
Clin Genet 1993: 43: 250–254. © Munksgaard, 1993
A family is described with X-linked congenital stationary night blindness of the complete type (CSNB1) in which clinical variation between affected males resulted in diagnostic difficulties. In two affected male cousins, one had congenital nystagmus and myopia, while the other was initially thought to have retinitis pigmentosa with optic atrophy and was hyperopic The diagnosis of X-linked congenital stationary night blindness was established by clinical, psychophysical and electrophysiological criteria, and DNA markers flanking the CSNB1 locus were analysed in the family. The results show that both affected males have inherited the same haplotype from their carrier mothers, excluding the possibility that a myopia gene in linkage disequilibrium with CSNB1 has recombined with this locus.     

Craniofacial anthropometric studies in Waardenburg syndrome type I

da-Silva EO, Batista JEM, Medeiros MAB, Fonteles SMS. Craniofacial anthropometric studies in Waardenburg syndrome type I.
Clin Genet 1993: 44: 20–25. © Munksgaard, 1993
A set of 15 surface measurements taken directly from the craniofacial region were determined in 51 patients with Waardenburg syndrome type I (WSI). A roentgencephamometric analysis including 20 linear dimensions was also performed by the use of cephalograms of 28 patients. Pairs between patients and controls of the same sex and age were established for comparison. The head circumference, clivus length and facial depth were smaller in affected individuals. The patients also had narrow nose, marked hypoplasia of the nasal bone, short philtrum, and short and retropositioned maxilla. A discriminant analysis revealed that the inner intercanthal distance, philtrum length, lower facial height and nasal bone length were excellent discriminating parameters of WSI.     

子宫畸形患者HOXA13基因同源结构域分析

目的探讨中国子宫畸形患者中HOXA13基因同源结构域是否存在突变及其相关性分析。方法国外文献报道手-足-生殖器综合征（hand-foot-genital syndrome,HFGS）患者中发现HOXA13基因2号外显子同源结构域存在点突变,而此综合征的女性患者部分症状表现为子宫畸形,因此对58例中国子宫畸形患者和54例正常对照者进行HOXA13基因同源结构域检测,PCR扩增目的片断后自动化测序分析基因2号外显子同源结构域区域。结果HOXA13基因同源结构域直接自动化测序分析结果显示,在患者和对照者中均没有突变发生。结论中国妇女子宫畸形的发生可能与HOXA13基因同源结构域突变无关。     

Familial bilateral antecubital pterygia with severe renal involvement in nail-patella syndrome

Rizzo R, Pavone L, Micali G, Hall JG. Familial bilateral antecubital pterygia with severe renal involvement in nail-patella syndrome.
Clin Genet 1993: 44: 1–7. © Munksgaard, 1993
A family in whom several members are affected with nail-patella dysplasia is reported because of severe renal involvement and bilateral antecubital pterygia. The family presented as arthrogryposis because of the elbow contractures.     

Birth prevalence,mutation rate,sex ratio,parents' age,and ethnicity in Apert syndrome

Apert syndrome was studied to determine birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity among 2,493,331 live births registered in the California Birth Defects Monitoring Program (CBDMP) from 1983 through 1993; 31 affected infants were identified. The sample was completed with an additional 22 cases from the Center for Craniofacial Anomalies (CCA), University of California, San Francisco, for a total of 53 affected children. Birth prevalence, calculated from the CBDMP subsample, was 12.4 cases per million live births (confidence interval [CI] 8.6,17.9). The calculated mutation rate was 6.2 × 10⁻⁶ per gene per generation. Asians had the highest prevalence (22.3 per million live births; CI 7.1,61.3) and Hispanics the lowest (7.6 per million, CI 3.3-16.4). In the large population-based CBDMP subsample, there was an almost equal number of affected males and females, (sex ratio 0.94) but in the clinical CCA subsample, there were more affected females (sex ratio 0.79). For all cases, the mean age of mothers was 28.9±6.0 years, and of fathers was 34.1±6.2 years. Almost half of fathers were older than 35 years when the child was born; for more than 20% of cases, both parents were older than 35 years. These findings may support the view that point mutations appear to be more commonly associated with paternal than with maternal alleles. Representing the largest systematically ascertained population-based study of Apert syndrome to date, they provide a reliable basis for genetic counseling and decision-making, and for focused research to define the cause of this syndrome. Am. J. Med. Genet. 72:394–398, 1997. © 1997 Wiley-Liss, Inc.     

Genetics of the female reproductive ducts

Familial aggregates of the most common disorders of müllerian differentiation in females-Müllerian aplasia, incomplete Müllerian fusion-are best explained on the basis of polygenic/multifactorial inheritance. No information exists on the number and chromosomal location of responsible genes. Single mutant genes (Mendelian) are responsible for the McKusick-Kaufman syndrome (MKS) and the hand-foot-genital syndrome. The molecular basis for the latter condition involves HOXA13, but the molecular basis of MKS and other disorders of the female reproductive ducts is unknown. Vaginal atresia, Müllerian aplasia, and incomplete Müllerian fusion are not infrequently observed in malformation syndromes.     

Mental retardation locus in Xp21 chromosome microdeletion

Xp21 microdeletion syndrome is associated with variable size Xp21 deletions that usually include the glycerol kinase locus. The clinical phenotypes we studied in this chromosome region include: Xpter – Åland Island eye disease (AIED) -adrenal hypoplasia (AH) -glycerol kinase (GKD) -Duchenne muscular dystrophy (DMD) -retinitis pigmentosa (RP) -ornithine transcarbamylase (OTC) -centromere. In a compilation of 18 individuals in 14 families with the AH, GKD, and DMD loci deleted, 17 were male and all were developmentally delayed. In contrast, we report mentally retarded female carriers in two Xp21 deletion syndrome families with DMD, GKD, and AH in affected males. In the first family with normal karyotypes, a submicroscopic deletion was associated with DMD in the retarded male and with retardation in carrier females. In the second family an X chromosome with a cytogenetically deleted Xp21 distal to the OTC and RP genes segregated in the affected male and retarded female carriers. DNA analysis at the DMD locus verified the cytogenetic findings. This report of mental retardation in otherwise asymptomatic female carriers of Xp21 deletion classifies one form of mental retardation in females. © 1993 Wiley-Liss, Inc.     

Distal arthrogryposis with autosomal dominant inheritance and reduced penetrance in females: the Gordon syndrome

Ioan DM, Belengeanu V. Maximilian C, Fryns JP. Distal arthrogryposis with autosomal dominant inheritance and reduced penetrance in females: the Gordon syndrome.
Clin Genet 1993: 43: 300–302. © Munksgaard, 1993
A family is reported in which camptodactyly, club foot, pectus excavatum and undescended testes are transmitted as an autosomal dominant with reduced penetrance and variable expressivity, affecting 13 members through five generations. Penetrance is more reduced in females than in males and asymptomatic carriers are always females. Similar findings were previously described in two other families reported by Gordon et al. (1962) and Halal & Fraser (1979).     

Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations

PurposeAutosomal recessive congenital short bowel syndrome is caused by mutations in CLMP. No mutations were found in the affected males of a family with presumed X-linked congenital short bowel syndrome or in an isolated male patient. Our aim was to identify the disease-causing mutation in these patients.MethodsWe performed mutation analysis of the second exon of FLNA in the two surviving affected males of the presumed X-linked family and in the isolated patient.ResultsWe identified a novel 2-base-pair deletion in the second exon of FLNA in all these male patients. The deletion is located between two nearby methionines at the N-terminus of filamin A. Previous studies showed that translation of FLNA occurs from both methionines, resulting in two isoforms of the protein. We hypothesized that the longer isoform is no longer translated due to the mutation and that this mutation is therefore not lethal for males in utero.ConclusionOur findings emphasize that congenital short bowel syndrome can be the presenting symptom in male patients with mutations in FLNA.Genet Med 2013:15(4):310–313     

Christ-Siemens-Touraine syndrome—a clinical and genetic analysis of a large Brazilian kindred: II. Affected males

We describe 13 males with Christ-Siemens-Touraine syndrome from one family. History and examination were supplemented by three sweat tests and dermatoglyphic analysis. Some of the patients had two uncommon findings (onychodystrophy and excessive lacrimation), and five had an “incomplete” form of the syndrome. Four signs (distal phalanges of fingers and toes radially and tibially deviated, respectively; facial hypochromic spots; large occipitofrontal circumference) seem to be here described for the first time. The segregation proportion in the sibships with at least an affected male was found to be normal (1:1) in 44 series of data (43 from the literature), where a high ascertainment bias was present ( 155 affected and 68 normal males).