12‐year‐old male with Elejalde syndrome (neuroectodermal melanolysosomal disease)

Neuroectodermal melanolysosomal disease, also known as Elejalde syndrome, is a rare syndrome characterized by silvery hair, pigment abnormalities, and profound central nervous system dysfunction. It is similar to the Chediak‐Higashi and Griscelli syndromes, although these syndromes are associated with severe immunologic dysfunction. We report on a 12‐year‐old male with Elejalde syndrome and compare the Elejalde, Chediak‐Higashi, and Griscelli syndromes. © 2001 Wiley‐Liss, Inc.     

Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle‐opathies with Microcephaly,Dwarfism and Skeletal Abnormalities

Co‐occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < ?3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier‐Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel‐like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral‐Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel‐like phenotype and FFS, the last of which has not been associated with any disease gene to date.     

Phenotypic overlap of McKusick‐Kaufman syndrome with Bardet‐Biedl syndrome: A literature review

Hydrometrocolpos (HMC) and post‐axial polydactyly (PAP) are common to both McKusick‐Kaufman syndrome (MKS) and Bardet‐Biedl syndrome (BBS). We review reported cases of MKS and BBS presenting with HMC and PAP early in life to determine if there are clinical features that allow discrimination between the two syndromes as the primary features of retinitis pigmentosa, obesity, learning disability in BBS are age‐dependent. We did not find any phenotypic features that allowed reliable differentiation between the two syndromes in the neonatal period. However, uterine, ovarian, and fallopian tube anomalies are more common in BBS patients, and it may be that these clinical features prove to be useful discriminating features. We conclude that sporadic female infants with HMC and PAP cannot be diagnosed with MKS until at least age 5 years and that monitoring for the complications of BBS should be performed in these patients. Am. J. Med. Genet. 95:208–215, 2000. Published 2000 Wiley‐Liss, Inc.     

Further delineation of Malan syndrome

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype‐phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall‐Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall–Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.     

The sixth international RASopathies symposium: Precision medicine—From promise to practice

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS‐mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life‐limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.     

PTEN: one gene,many syndromes

PTEN, on 10q23.3, encodes a major lipid phosphatase which signals down the phosphoinositol-3-kinase/Akt pathway and effects G1 cell cycle arrest and apoptosis. Germline PTEN mutations have been found to occur in 80% of classic Cowden syndrome (CS), 60% of Bannayan-Riley-Ruvalcaba syndrome (BRRS), up to 20% of Proteus syndrome (PS), and approximately 50% of a Proteus-like syndrome (PSL). CS is a heritable multiple hamartoma syndrome with a high risk of breast, thyroid, and endometrial carcinomas. BRRS is a congenital autosomal dominant disorder characterized by megencephaly, developmental delay, lipomatosis, and speckled penis. PS and PSL had never been associated with risk of malignancy. Finding germline PTEN mutations in patients with BRRS, PS, and PSL suggests equivalent risks of developing malignancy as in CS with implications for medical management. The mutational spectra of CS and BRRS overlap, with many of the mutations occurring in exons 5, 7, and 8. Genotype-phenotype association analyses have revealed that the presence of germline PTEN mutations is associated with breast tumor development, and that mutations occurring within and 5' of the phosphatase motif were associated with multi-organ involvement. Pooled analysis of PTEN mutation series of CS and BRRS occurring in the last five years reveals that 65% of CS-associated mutations occur in the first five exons encoding the phosphatase domain and the promoter region, while 60% of BRRS-associated mutations occur in the 3' four exons encoding mainly the C2 domain. Somatic PTEN mutations occur with a wide distribution of frequencies in sporadic primary tumors, with the highest frequencies in endometrial carcinomas and glioblastoma multiform. Several mechanisms of PTEN inactivation occur in primary malignancies derived from different tissues, but a favored mechanism appears to occur in a tissue-specific manner. Inappropriate subcellular compartmentalization and increased/decreased proteosome degradation may be two novel mechanisms of PTEN inactivation. Further functional work could reveal more effective means of molecular-directed therapy and prevention.     

Perthes disease: A new finding in Floating‐Harbor syndrome

Floating‐Harbor Syndrome (FHS; OMIM #136140) is an ultra‐rare autosomal dominant genetic condition characterized by expressive language delay, short stature with delayed bone mineralization, a triangular face with a prominent nose, and deep‐set eyes, and hand anomalies. First reported in 1973, FHS is associated with mutations in the SRCAP gene, which encodes SNF2‐related CREBBP activator protein. Mutations in the CREBBP gene cause Rubinstein‐Taybi Syndrome (RSTS; OMIM #180849, #613684), another rare disease characterized by broad thumbs and halluces, facial dysmorphisms, short stature, and intellectual disability, which has a phenotypic overlap with FHS. We describe a case of FHS associated with a novel SRCAP mutation and characterized by Perthes disease, a skeletal anomaly described in approximately 3% of patients with RSTS. Thus Perthes disease can be added to the list of clinical features that overlap between FHS and RSTS.

     

MCA syndrome with renal‐hepatic‐pancreatic dysplasia,posterior fossa cyst,symmetrical limb deficiencies,cleft palate,cardiac and Müllerian duct anomalies

Angelman syndrome (AS) is a disorder of psychomotor development caused by loss of function of the imprinted UBE3A gene. Since the paternal UBE3A copy is regularly silent, only mutations inactivating the maternal copy cause AS. Among 1,272 patients suspected of AS, we found one with an isolated deletion of the UBE3A gene on the maternally inherited chromosome. Initial DNA methylation testing at the SNURF‐SNRPN locus in the patient revealed a normal pattern. The deletion was only detected through allelic loss at microsatellite loci D15S1506, D15S122, and D15S210, and confirmed with fluorescence in situ hybridization (FISH) using bacterial artificial chromosome (BAC) probes derived from the loci. It extends approximately 570 kilobase pairs (kbp), encompassing the UBE3A locus, and is flanked by loci PAR/SN and D15S986. The deletion is familial, and haplotype studies suggest that a great grandfather of the index patient already carried this deletion, and that it causes AS when inherited through the female germline but not Prader‐Willi syndrome (PWS) when paternally inherited. Our findings support the hypothesis that the functional loss of maternal UBE3A gene activity is sufficient to cause AS and that the deleted region does not contain genes or other structures that are involved in PWS. Finally, this case highlights that methylation tests can fail to detect some familial AS cases with a recurrence risk of 50%. © 2002 Wiley‐Liss, Inc.     

Mutation analysis and description of sixteen RSH/Smith‐Lemli‐Opitz syndrome patients: Polymerase chain reaction–based assays to simplify genotyping

We report the clinical and molecular data of 16 patients with RSH/Smith‐Lemli‐Opitz syndrome (RSH/SLOS) with varying phenotypic severity, for which we have identified mutations in both alleles. RSH/SLOS is an autosomal recessive malformation syndrome caused by mutations in the gene encoding the sterol Δ⁷‐reductase. This protein catalyzes the reduction of 7‐dehydrocholesterol to cholesterol in the last step of cholesterol biosynthesis via the Kandutsch‐Russell pathway. In addition to previously reported mutations (T93M, L109P, G147D, W151X, T154M, R242C, A247V, T289I, IVS8‐1G→C, Y408H, and E448K), we have identified six previously undescribed mutations (321G→C, W177R, R242H, Y318N, L341P, and C444Y). We also report rapid polymerase chain reaction (PCR)–based assays developed to detect four of the recurring mutations (T93M, W151X, V326L, and R404C) and six other RSH/SLOS mutations (321G→C, L109P, T154M, T289I, Y318N, and L341P). The purpose of this article is to correlate detailed clinical information with molecular data in order to improve our understanding of the genotype–phenotype correlation of RSH/SLOS and to report the development of PCR‐based assays that will allow more rapid mutation analysis. Am. J. Med. Genet. 94:214–227, 2000. Published 2000 Wiley‐Liss, Inc.     

PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature

PTEN hamartoma tumor syndrome (PHTS) is a highly variable autosomal dominant condition associated with intellectual disability, overgrowth, and tumor predisposition phenotypes, which often overlap. PHTS incorporates a number of historical clinical presentations including Bannayan‐Riley‐Ruvalcaba syndrome, Cowden syndrome, and a macrocephaly‐autism/developmental delay syndrome. Many reviews in the literature focus on PHTS as an adult hamartoma and malignancy predisposition condition. Here, we review the current literature with a focus on pediatric presentations. The review starts with a summary of the main conditions encompassed within PHTS. We then discuss PHTS diagnostic criteria, and clinical features. We briefly address rarer PTEN associations, and the possible role of mTOR inhibitors in treatment. We acknowledge the limited understanding of the natural history of childhood‐onset PHTS as a cancer predisposition syndrome and present a summary of important management considerations.     

Novel 7‐DHCR mutation in a child with Smith‐Lemli‐Opitz syndrome

Smith‐Lemli‐Opitz syndrome (SLOS) is an autosomal recessive disorder characterized by minor facial anomalies, mental retardation, and multiple congenital abnormalities. Biochemically, the disorder is caused by deficient activity of 7‐dehydrocholesterol reductase, which catalyzes the reduction of the Δ7 double bond of 7‐dehydrocholesterol to produce cholesterol. Recently, mutations in the gene encoding 7‐dehydrocholesterol reductase (7DHCR) were found to cause SLOS. We report the first molecular characterization of an Italian SLOS patient. Interestingly, his paternal 7DHCR allele, of Arab origin, harbored a novel P329L mutation which in combination with a maternal splice‐site (IVS8‐1 G>C) mutation resulted in a relatively milder phenotype. Am. J. Med. Genet. 91:138–140, 2000. © 2000 Wiley‐Liss, Inc.     

A novel homozygous missense mutation (c.610G>A, p.Gly204Ser) in the WNT7A gene causes tetra-amelia in two Saudi families

Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel (AA/RRS) phocomelia syndrome are rare autosomal recessive inherited disorders characterized by aplastic/hypoplastic nails with ectopic dorsal palms, absence of humeri, hypoplastic ulnae, and bowed short radii with the elbow joints present, shown to result from missense mutations in WNT7A (p.Ala109Thr and p.Arg292Cys). Here, we describe three affected individuals belonging to two related Saudi Arabian families. All three have a similar phenotype characterized by pelvic dysplasia and truncated lower limbs compatible with the clinical diagnosis of AA/RRS. The upper limbs were more variable: one patient individual had complete amelia, whereas the others had variable limb malformations and all had absence of nails and the ventralization of the palms/digits. All affected individuals were homozygous for a mutation in exon 4 of WNT7A (c.610G>A) resulted in substitution of a highly conserved glycine to serine (p.Gly204Ser) within the Wnt signature motif [C-K-C-H-G-V-S-G-S-C]. This report describes a third cases/family in the literature with variable phenotype of AA/RRS and Fuhrmann syndrome. Identification of this mutation further underlines the crucial involvement of WNT7A in the limb development. This novel missense homozygous mutation (p.Gly204Ser) in the WNT7A gene is a unique mutation in the degree of loss of function in the upper limb development which ranges from mild to complete absence of both upper limbs (amelia). Moreover, all three affected individuals had genitourinary anomalies, linking WNT7A function to genitourinary development.     

Expanding the spectrum of CEP55‐associated disease to viable phenotypes

Homozygosity for nonsense variants in CEP55 has been associated with a lethal condition characterized by multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly (MARCH syndrome) also known as Meckel‐like syndrome. Missense variants in CEP55 have not previously been reported in association with disease. Here we describe seven living individuals from five families with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. Here we compare our seven patients with three previously reported families with a prenatal lethal phenotype (MARCH syndrome/Meckel‐like syndrome) due to homozygous CEP55 nonsense variants. Our series suggests that individuals with compound heterozygosity for nonsense and missense variants in CEP55 have a different viable phenotype. We show that homozygosity for a splice variant near the end of the CEP55 gene is also compatible with life.