A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome.

Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling.

Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome.

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.

Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations.

Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome.

Microcephaly-capillary malformation (MIC-CAP) syndrome is characterized by severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We used whole-exome sequencing of five patients with MIC-CAP syndrome and identified recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM) that has a key role in cell surface receptor-mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways.

Deletions and duplications of developmental pathway genes in 5q31 contribute to abnormal phenotypes.

Although copy number changes of 5q31 have been rarely reported, deletions have been associated with some common characteristics, such as short stature, failure to thrive, developmental delay (DD)/intellectual disability (ID), club feet, dislocated hips, and dysmorphic features. We report on three individuals with deletions and two individuals with duplications at 5q31, ranging from 3.6 Mb to 8.

A new syndrome with multiple capillary malformations, intractable seizures, and brain and limb anomalies.

We present two unrelated male infants with strikingly similar clinical features which have not previously been reported together. The most unusual feature was the presence of multiple small capillary malformations (port-wine stains) on the skin from birth. Both infants had intractable seizures, microcephaly with progressive cortical atrophy, severe developmental delay, dysmorphic facial features, and hypoplasia of the distal phalanges.

Diagnosing xeroderma pigmentosum group C by immunohistochemistry.

Xeroderma pigmentosum (XP) is a group of rare inherited human neurocutaneous diseases, and the group C (XPC) is the major group of patients with XP in Europe, North America, and South America. Current molecular diagnostic methods for XP require specialized, expensive, and time-consuming UV sensitivity and DNA repair assays followed by gene sequencing. To determine whether immunohistochemistry (IHC) would be a robust alternative method to diagnose patients with XPC, we stained sections of paraffin-embedded skin biopsies for XPC by IHC, using 69 archived blocks from confirmed or clinically suspect patients with XPA, XPC, XPD, XPE, and without XP.

Limb hyperplasia: case report of an unusual variant of Klippel-Trenaunay syndrome and review of the literature.

Klippel-Trenaunay syndrome (KTS) is a rare disorder involving a triad of cutaneous capillary malformations (port-wine stain), varicose veins or venous malformations, and bony or soft tissue hyperplasia of an extremity. It is one of many heterogeneous disorders known as overgrowth syndromes that are characterized by either generalized or localized somatic overgrowth. Overgrowth syndromes each have unique clinical, behavioral, and genetic features, but some of these features overlap, causing diagnostic difficulty.

Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia.

Isolated hemihyperplasia, formerly termed isolated hemihypertrophy, is a congenital overgrowth disorder associated with an increased risk for embryonal tumors, mainly Wilms tumor and hepatoblastoma. This practice guideline will set forth the diagnostic criteria and tumor screening recommendations for children with isolated hemihyperplasia, based on the best information available. There is clinical overlap between isolated hemihyperplasia with Beckwith-Wiedemann syndrome.

Acute lymphoblastic leukemia in a patient with Miller-Dieker syndrome.

A 15-month-old girl with Miller-Dieker syndrome, a contiguous gene deletion syndrome involving chromosome 17p13.3 and resulting in lissencephaly, was diagnosed with precursor B-cell acute lymphoblastic leukemia. Cytogenetic analysis identified both the previously detected 17p13.

Two new patients with Curry-Jones syndrome with trichoblastoma and medulloblastoma suggest an etiologic role of the sonic hedgehog-patched-GLI pathway.

Curry-Jones syndrome (OMIM #601707) is a rare multiple malformation disorder of unknown etiology, associated with brain and skull abnormalities, polysyndactyly, and defects of the eyes, skin and gastrointestinal tract. We report on two new cases of Curry-Jones syndrome with previously unreported features, including benign and malignant neoplasms. The first patient had typical features of Curry-Jones syndrome as well as multiple intra-abdominal smooth muscle hamartomas and trichoblastoma of the skin.

Pierre Robin sequence associated with first trimester fetal tamoxifen exposure.

Tamoxifen is a nonsteroidal antiestrogen used as the current adjuvant endocrine treatment of choice for premenopausal women treated for breast cancer and its potential for causing fetal harm during pregnancy remains inconclusive. While the evidence of tamoxifen's effects on humans in utero is minimal, animal studies have shown evidence of teratogenicity, hence the FDA's class D categorization of the drug. In 1994 Cullins et al.

Neuroimaging findings in macrocephaly-capillary malformation: a longitudinal study of 17 patients.

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly-Capillary Malformation (M-CM). This syndrome has been traditionally known as Macrocephaly-Cutis Marmorata Telangiectatica Congenita (M-CMTC), but we explain why M-CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases.

Deaths due to choking in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is the most common known syndromic cause of life-threatening obesity, yet few studies have examined the causes of death in PWS. The objective of this study was to examine the contribution of choking leading to mortality in PWS. In 1999, a brief survey was made available from the Prader-Willi Syndrome Association (USA) bereavement program, which documented demographic data and causes of death.

Risk for leukemia in infants without Down syndrome who have transient myeloproliferative disorder.

Transient myeloproliferative disorder (TMD) occurs in 10% of infants with Down syndrome (DS). Down syndrome infants with resolved TMD may later develop acute megakaryocytic leukemia (AMKL). In these patients, AMKL is associated with somatic mutations in the X-linked transcription factor gene, GATA1.

Marshall-Smith syndrome: natural history and evidence of an osteochondrodysplasia with connective tissue abnormalities.

The Marshall-Smith syndrome (MSS) is a distinct malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia. At least 33 cases have been reported in the literature, mostly as single case reports or small series. The purpose of the present study is to report on the clinical findings and natural history of MSS in five children and to review the features of three others previously reported, with particular attention to the skeletal and connective tissue findings.

Unexpected death and critical illness in Prader-Willi syndrome: report of ten individuals.

Individuals with Prader-Willi syndrome (PWS) generally survive into adulthood. Common causes of death are obesity related cor pulmonale and respiratory failure. We report on a case series of eight children and two adults with unexpected death or critical illness.

Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia.

An elevated risk of hepatoblastoma for children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia is well established. We describe five children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia for whom serial serum alpha-fetoprotein screening, usually in combination with abdominal ultrasound, led to early detection of hepatoblastoma.

Athabascan brainstem dysgenesis syndrome.

We report a new disorder with diverse neurological problems resulting from abnormal brainstem function. Consistent features of this disorder, which we propose should be called the Atabascan brainstem dysgenesis syndrome, include horizontal gaze palsy, sensorineural deafness, central hypoventilation, and developmental delay. Other features seen in some patients include swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, and cardiac outflow tract anomalies.