Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy-like phenotype.

A minority of the reported cases of terminal 2q37 deletion clinically resemble Albright hereditary osteodystrophy (AHO)/pseudopseudohypoparathyroidism and have only mild-to-moderate mental retardation. Our molecular and cytogenetic fluorescence in situ hybridization (FISH) findings on an additional three patients further reduce the size of the minimal critical region deleted in this syndrome to about 3 Mb. This region includes the G-protein-coupled receptor 35 (GPR35), glypican 1 (GPC1), and serine/threonine protein kinase 25 (STK25) genes on 2q37.3. We have further defined several polymorphic variants within the coding region and flanking regions of GPR35 gene, which could potentially be useful for rapid detection of GPR35 gene deletion. We postulate that the absence of GPR35 may, at least partly, account for the phenotypic resemblance to the AHO. We also believe that the deletion of GPR35 could be responsible for the entity brachydactyly mental retardation syndrome (OMIM #600430), which was coined based on the above minority of patients with terminal 2q37 deletion. We recommend that every patient with AHO phenotype should undergo 2q subtelomeric FISH screen and subsequently a molecular study on the GPR35 gene. GPC1 and/or STK25 haploinsufficiency may also contribute to the AHO-like phenotype.

Twin brothers with MIDAS syndrome and XX karyotype.

Twin brothers with microphthalmia, facial dermal hypoplasia, sclerocornea, and supraventricular tachycardia, are reported. Their clinical features are compatible with MIDAS syndrome, a known X-linked and hemizygous male lethal condition. Their karyotypes showed an XX sex chromosome modality with a subtle Xp/Yp translocation proven by the presence of SRY gene. The pregnancy was complicated with fetal supraventricular tachycardia, which was treated with digoxin prenatally. Postnatally, both twins required treatment with adenosine, digoxin, and propanolol to remain in normal sinus rhythm. The possible involvement of the heart, only in the form of cardiomyopathy with arrhythmia is emphasized. Both twins had a selective X-inactivation of the derivative chromosome X with Xp/Yp translocation.

New syndrome characterized by sparse hair, prominent nose, small mouth, micrognathia, cleft palate, crumpled upper helices, digit anomaly, and mild developmental delay.

A brother and a sister show very similar clinical features, including sparse hair in the first year of life, prominent nose, small mouth, micrognathia, high arched palate or cleft palate, crumpled upper helices, flexion limitation of the distal interphalangeal joint of the fingers, and mild developmental delay. Their clinical appearance suggests a premature aging phenotype, but is not really compatible with the hitherto known syndromes of that group. The mode of inheritance is likely autosomal recessive.

Syndrome of short stature, widow's peak, ptosis, posteriorly angulated ears, and joint problems: exclusion of the Aarskog (FGD1) gene as a candidate gene.

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.

Mapping of a gene (MRXS9) for X-linked mental retardation, microcephaly, and variably short stature to Xq12-q21.31.

Three boys from two families were identified as having a syndrome of X-linked mental retardation (XLMR) with microcephaly and short stature, clinically resembling Renpenning syndrome but with normal size of testicles in affected men. When the effort to map the gene for the above condition was initiated, it was realized that the two families were actually related to each other. Over 50 polymorphic markers of known locations along the X chromosome were scored in this family in a study to map the disease gene. Nine affected and four unaffected males were genotyped to produce a maximum LOD score of 4.42 at zero recombination with markers in proximal Xq. The results indicate that the gene responsible for this disorder is located in the cytogenetic Xq12 to Xq21.31 interval of the X chromosome within a section of chromosome of about 17 cM between the AR and DXS1217 loci over some 25 mb. Since the gene for the X-linked mental retardation from the original Saskatchewan family described by Renpenning [Renpenning et al., 1962: Can Med Assoc J 87:954-956; Fox and Gerrard, 1980: Am J Med Genet 7:491-495] was recently mapped to a different nonoverlapping region [Stevenson et al., 1998: Am J Hum Genet 62:1092-1101] this would appear to be a separate disorder.

Delineation of 14q32.3 deletion syndrome.

A patient with a 14q32.3 terminal band deletion and cat cry is reported. Review of four other 14q32.3 deletion cases suggests the possible presence of a recognisable 14q32.3 terminal deletion syndrome, which is characterised by (1) apparently postnatal onset of small head size in comparison to body size, (2) high forehead with lateral hypertrichosis, (3) epicanthic folds, (4) broad nasal bridge, (5) high arched palate, (6) single palmar crease, and (7) mild to moderate developmental delay. Although none of the above seven features in unique to this syndrome, and indeed are quite common in other chromosomal disorders or genetic syndromes, patients with a terminal 14q32.3 deletion do show a recognisable facial gestalt. Interestingly, unlike ring chromosome 14, the 14q32.3 terminal deletion has rarely been reported, possibly because it is harder to detect, and an optimal chromosome preparation is required for its identification.

beta-Glucuronidase P408S, P415L mutations: evidence that both mutations combine to produce an MPS VII allele in certain Mexican patients.

Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is an autosomal recessively inherited lysosomal storage disease caused by a deficiency in beta-glucuronidase. We identified and studied a novel allele containing two C-to-T transitions resulting in P408S and P415L alterations, which is present in homozygous state in one Mexican patient and in heterozygous state in another. None of the previous reports describing mutations in the MPS VII gene include Mexican patients. Expression of either of the mutations individually showed only modest effects on the properties of the enzyme. However, expression of the doubly mutant allele resulted in markedly reduced activity and rapid degradation in an early biosynthetic compartment.

Interstitial 6q deletion and Prader-Willi-like phenotype.

A third case of an interstitial deletion of the long arm of chromosome 6 with clinical features mimicking Prader-Willi syndrome (PWS) is presented. Although preliminary clinical evaluation in each case suggested PWS, further review revealed that the features in all three cases are not completely compatible with the characteristic findings in Prader-Willi syndrome. Furthermore, the deletions in the three cases do not show a consistent region of overlap. Consequently, no particular band or region in 6q can be defined as associated with obesity. However, our findings confirm the suggestion of Villa et al. in 1995, that individuals with a PWS phenotype who are cytogenetically and molecularly negative for a deletion of 15q11-q13 should be examined for a deletion of 6q.

Linear disruption of umbilical cord: a rare anomaly of the cord associated with acute fetal distress and perinatal death/profound psychomotor retardation.

We report on a non-malformed child with severe microcephaly and profound psychomotor delay. Review of the delivery/birth records documented descriptions consistent with linear disruption of the umbilical cord. This rare anomaly typically leads to acute fetal distress and perinatal death. Severe microcephaly and psychomotor delay without other anomalies should prompt a careful review of the delivery/birth records to search for umbilical cord descriptions consistent with this diagnosis.

Autosomal dominant transmission of familial laterality defects.

Heterotaxy results from failure to establish normal left-right asymmetry during embryonic development. Most familial cases are thought to be autosomal recessive. We have identified a family in which 4 individuals from 3 generations manifest laterality defects. Twenty-five family members have been examined. Two have complete reversal of normal laterality (situs inversus) while 2 others have asplenia, midline liver, and complex cardiac malformations (situs ambiguus). Two additional obligate gene carriers are anatomically normal (situs solitus). Male-to-male transmission confirms autosomal inheritance. Identification of this family establishes an autosomal dominant form of laterality defect, suggesting that a portion of sporadic cases may be new-mutation dominant or unrecognized familial cases. The finding of all forms of laterality (solitus, ambiguus, and inversus) among obligate disease gene carriers within a single family may be relevant to genetic evaluation and counseling in apparently isolated patients with laterality disturbance.

Four new cases of inverted terminal duplication: a modified hypothesis of mechanism of origin.

We present 4 recently diagnosed cases of inverted tandem duplication with involvement of the respective terminal band. Based on these 4 cases and review of the literature, the term "inverted terminal duplication" is proposed to designate specifically the type of inverted tandem duplication which involves the terminal band. A modification of the previous hypothesis of mechanism of origin is advanced. It is speculated further that a telomeric deletion of a meiotic chromosome followed by a U-type reunion of the chromatids, considered to be the first steps of the proposed mechanism of origin, may not be a rare gonadal event.

Supernumerary isochromosome 4p in ANLL-M4 myelomonocytic type is associated with favorable prognosis.

A case of an acute non-lymphocytic leukemia of M4 type with a supernumerary isochromosome (4p) in 100% of the initial bone marrow metaphase cells is reported. The origin of the extra chromosome is verified by the fluorescence in situ hybridization technique using a whole chromosome 4 painting probe. A possible favorable prognosis of the ANLL-M4 case showing a supernumerary isochromosome (4p) is cautiously emphasized.

3C (cranio-cerebello-cardiac) syndrome: a recently delineated and easily recognizable congenital malformation syndrome.

We report on two cases of 3C (cranio-cerebello-cardiac) syndrome. At least five previous cases are known. This recently delineated malformation syndrome is characterized by congenital anomalies of the skull, hindbrain, and heart. The anomalies include a high and prominent forehead, a hypoplastic vermis and posterior fossa cyst with or without hydrocephalus, and an atrial or atrio-ventricular septal defect with or without other heart anomalies. Most patients show a postnatal growth retardation, as well as a mild to moderate psychomotor retardation. Early death is usually in association with severe congenital heart defect. Aside from two affected sisters, the other reported cases (four girls and one boy) are sporadic cases; thus, a possible genetic nature and inheritance mode remain uncertain. Nonetheless, the possibility of an autosomal recessive mode of inheritance should be considered in the genetic counselling.

Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome.

We evaluated the families of 50 children with idiopathic congenital central hypoventilation syndrome (CCHS) to 1) test genetic hypotheses, 2) explore the relationship to Hirschsprung disease (HD), and 3) examine other clinical findings including sudden infant death syndrome (SIDS) in relatives of CCHS patients. A questionnaire was administered to parents of each proband to determine a detailed pedigree and medical history for 3 generations including 1,482 relatives. The data were analyzed under the unified mixed model method (assumes individual genotype composed of multifactorial [MF] and major locus [ML] components). Analysis was made of the Total dataset and on subdivided data sets: HIR1 = families of probands with HD (n = 8) vs. HIR2 = families of probands without HD; then under a premise that severe, chronic constipation may be a milder form of HD (i.e., ganglion cells present but dysfunctional), CON1 = families of probands with HD or constipation (n = 13) vs. CON2 = families of probands without HD or constipation. By statistical genetic analysis of the Total, HIR1, and CON1 datasets, the MF and ML hypotheses were about equally likely, with the MF model slightly more parsimonious. Although HIR2 and CON2 datasets indicated no familiality, statistical evidence of heterogeneity between the results of HIR1 and HIR2, or between CON1 and CON2 was lacking. A SIDS incidence of 11.2/1,000 was documented among the relatives of CON1 vs. 1.8/1,000 among relatives of CON2. Our results are consistent with familiality by either MF or ML models. Recurrence risk is likely < 5%. The relationship of CCHS to the high familial incidence of SIDS is intriguing and demands further investigation.

Evidence of chromosome 9 origin of the euchromatic variant band within 9qh.

Fluorescence in-situ hybridization studies using a whole chromosome 9 painting probe were performed on three individuals from two different families, who carry a chromosome 9 variant with an extra band within the elongated 9qh region. The results confirm the euchromatic nature of the extra band, and provide evidence that it is of chromosome 9 origin. This variant band, which may not be very rare, thus possibly results from a duplication of a segment of 9qh plus band p12 or part of band q21.