Recurrence risk in the Angelman (“happy puppet”) syndrome

We report on two sibs with Angelman “happy puppet” syndrome. Out of 48 families reported in the literature, this is only the fourth family with affected sibs. A review of the literature shows a low but not negligible recurrence risk. Different explanations for this are discussed.     

Duplication 12q mosaicism in two unrelated patients with a similar syndrome

Two unrelated children with a similar syndrome were found to have mosaicism for a cell line containing one chromosome 12 with an additional faintly G-banding staining region that apparently represents a duplication of the distal portion of the long arm. The homolog and the other chromosomes are normal, as are the parental chromosomes. The remarkable phenotypic similarity of the 2 patients and their resemblance to 2 previously reported patients with duplication of the same chromosome region suggests that duplication 12q24 results in a clinically identifiable malformation syndrome.     

A novel phenotype characterized by digital abnormalities,intellectual disability,and short stature in a Mexican family maps to Xp11.4–p11.21

The family observed in this study included affected males and asymptomatic females. The patients shared specific digital abnormalities including postaxial polydactyly, cutaneous syndactyly, and brachydactyly. In addition, the patients exhibited mild‐to‐moderate intellectual disability and short stature coupled with microbrachycephaly, scoliosis, and cerebellar and renal hypoplasia. No chromosomal alterations or copy number variations were found in the index case. The genetic linkage analysis, which focused on the X chromosome, and the haplotype analysis detected a ～15.74 Mb candidate region located at Xp11.4–p11.21 with a LOD score of 4.8. Additionally, half of the mothers showed skewed X‐inactivation, while the other mothers exhibited random inactivation patterns. The candidate region includes 28 protein‐encoding genes that have not yet been implicated in human disorders. We speculate that the observed phenotype is compatible with a monogenic disorder in which the mutant gene plays a significant role during embryonic development. Based on the patients' clinical features, image studies, pedigree, chromosome location, and X‐inactivation studies in the mothers, we propose that this family has a novel, specific syndrome with an X‐linked recessive mode of inheritance. © 2013 Wiley Periodicals, Inc.     

A case of de novo i(12p) with 12q whole-arm translocation mosaicism

We report a dup(12p) due to a de novo i(12p) in a girl with mosaicism for 12q whole-arm translocations onto 7p, 7q, and 11q terminal regions. The dup(12p) syndrome was confirmed by clinical, cytogenetic, and LDH-dosage studies.     

Duplication 10p in a girl due to a maternal translocation t(10;14) (p11:p12)

We present a dup (10p) due to a t(10;14) (p11;p12)mat with a malformation syndrome in a girl. The analysis of 37 published cases shows that 31 patients (16 ♂; 15 ♀) had either a mother or a father carrying a balanced translocation; one case was due to a paternal and another due to a maternal pericentric inversion; two cases were due to de novo translocations; one case had a partial duplication of 10p; and one case had a supernumerary ring chromosome composed of 10p material. The phenotypic spectrum of the condition was analyzed. It is a specific multiple congenital anomalies/mental retardation (MCA/MR) syndrome which includes characteristic facial appearance (dolichocephaly, frontal bossing, short nose with a broad root, highly arched and upswept eyebrows, long philtrum, and thin lips), postnatal growth retardation, severe mental and psychomotor retardation, and several major and minor anomalies. Pseudohermaphroditism seems to be an important anomaly being present in 15 to 20% of affected males. A hypothenar crease together with a transverse crease forming a “crease triangle” seems a helpful sign in the clinical diagnosis of duplication 10p.     

MID1 mutation screening in a large cohort of Opitz G/BBB syndrome patients: twenty-nine novel mutations identified

Opitz G/BBB Syndrome (OS) is a multiple congenital anomaly disorder characterized by defects along the body midline. The disease is characterized by variable expressivity of signs that include hypertelorism, cleft lip and/or palate, laryngo-tracheo-esophageal abnormalities, cardiac defects, and hypospadias. OS patients also present with mental retardation and brain anatomical abnormalities. An autosomal dominant form mapping to chromosome 22 and an X-linked form of OS are known. The gene responsible for the X-linked form of OS, MID1, codes for a member of the Tripartite Motif family of E3 ubiquitin ligases. Here we report 29 novel mutations in 29 unrelated patients of a cohort of 140 male OS cases. These mutations are found in both familial and sporadic cases. They are scattered along the entire length of the gene and are represented by missense and nonsense mutations, insertions and deletions causing frame shift mutations, and deletion of either single exons or the entire gene. The variety of the mutations found confirms that loss-of-function is the mechanism underlying the OS phenotype. Moreover, the low percentage of MID1-mutated OS patients, 47% of the familial and 13% of the sporadic cases, suggests a wider genetic heterogeneity underlying the OS phenotype.     

Pathologic findings in the Wolf-Hirschhorn (4p-) syndrome

We describe a 1-month-old female with the Wolf-Hirschhorn syndrome. GTG-banding studies disclosed a 46,XX,del(4)(:p15 → qter) in the child and apparently normal chromosomes in the parents. Autopsy at 4 months showed hypoplasia of most organs.     

The dup(17p) syndrome

In a 42-month-old girl a duplicated 17p chromosome anomaly was identified by trypsin-Giemsa banding techniques. The clinical findings are compared with those of previous case reports. Common phenotypics changes include failure to thrive; hypoplastic, apparently low-set ears; micrognathia; flexion abnormalities of fingers; and foot abnormalities.     

Missense mutation in PAK3, R67C,causes X‐linked nonspecific mental retardation

X‐linked mental retardation is a very common condition that affects approximately 1 in 600 males. Despite recent progress, in most cases the molecular defects underlying this disorder remain unknown. Recently, a study using the candidate gene approach demonstrated the presence of mutations in PAK3 (p21‐activating kinase) associated with nonspecific mental retardation. PAK3 is a member of the larger family of PAK genes. PAK proteins have been implicated as critical downstream effectors that link Rho‐GTPases to the actin cytoskeleton and to MAP kinase cascades, including the c‐Jun amino‐terminal kinase (JNK) and p38. We screened 12 MRX pedigrees that map to a large region overlying Xq21‐q24. Mutation screening of the whole coding region of the PAK3 gene was performed by using a combination of denaturing gradient gel electrophoresis and direct sequencing. We have identified a novel missense mutation in exon 2 of PAK3 gene (R67C) in MRX47. This confirms the involvement of PAK3 in MRX following the report of a nonsense mutation recently reported in MRX30. In the MRX47 family, all affected males show moderate to severe mental retardation. No seizures, statural growth deficiency, or minor facial or other abnormal physical features were observed. This mutation R67C is located in a conserved polybasic domain (AA 66–68) of the protein that is predicted to play a major role in the GTPases binding and stimulation of Pak activity. Am. J. Med. Genet. 93:294–298, 2000. © 2000 Wiley‐Liss, Inc.     

Duplication 2q33→2q37 due to paternal ins (12;2) translocation

An 18 month-old boy with partial duplication of the long arm of chromosome 2, based on a paternal balanced translocation, 46,XY,ins (12,2)(q23;q33q37), is described and compared with five previously reported cases. These children have in common a short nose with broad flat bridge and small anteverted nostrils, long upper lip, low-set ears, and minor digital anomalies.     

Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome

Tint et al. [N Engl J Med 1994, 330:107–113], working with blood samples from the Smith-Lemli-Opitz syndrome (SLOS) patients of Irons and Elias showed the biochemical basis of this disorder to be a cholesterol biosynthesis defect [Irons et al., Lancet, 1993, 341:1414]. Based on this finding, clinical protocols for cholesterol and bile acid replacement therapy were established in a few centers including the University of Pittsburgh. We report our experience with bile acid and/or cholesterol replacement therapy in six patients with SLOS, now aged 3–27 years, with a confirmed biochemical diagnosis. Levels of plasma cholesterol and 7-dehydrocholesterol were correlated with periodic clinical evaluations over 8–27 months of therapy. There was a marked improvement in the growth of all the children. There was also an increase in the plasma cholesterol level in all the children and an overall increase in their percent sterol as cholesterol. Subjective improvement was also noted in their development. Although there was no significant change in the plasma cholesterol level of the older patients, there was a marked improvement in their behavior and in their quality of life. Am. J. Med. Genet. 68:315–321, 1997. © 1997 Wiley-Liss, Inc.     

dup(4p 15→4pter) in a 19-year-old woman resulting from a maternal 4;14 translocation

We describe a 19-year-old woman who has a duplication of 4p. The karyotype is 46,XX, – 14, + der(14),t(4;14) (p15;p12)mat in lymphocytes and skin fibroblasts. The patient has coarse hair, prominent forehead and tip of nose, coloboma, scoliosis, and mental retardation.     

Cardio-Facio-cutaneous (CFC) syndrome: Report of two patients without hyperkeratotic skin lesions

We report on two boys with the cardio-facio-cutaneous (CFC) syndrome, but without hyperkeratotic skin involvement. They showed most of the manifestations of the CFC syndrome: growth and developmental retardation, relative macrocephaly, distinct facial appearance, sparse hair, and heart defects. Their skin was not hyperkeratotic, but patient 1 had mild atopic dermatitis and keloid-like depigmented spots.