Structural rearrangements as a recurrent pathogenic mechanism for SETBP1 haploinsufficiency.

Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype-phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions. We report about three non-related individuals, harboring chromosomal structural rearrangements interrupting SETBP1, leading to gene haploinsufficiency. Two out of them resulted negative to Chromosomal Microarray Analysis (CMA), being the rearrangement balanced at a microarray resolution. The third one, presenting with a complex three-chromosome rearrangement, had been previously diagnosed with SETBP1 haploinsufficiency due to a partial gene deletion at one of the chromosomal breakpoints. We thoroughly characterized the rearrangements by means of Optical Genome Mapping (OGM) and Whole Genome Sequencing (WGS), providing details about the involved sequences and the underlying mechanisms. We propose structural variants as a recurrent event in SETBP1 haploinsufficiency, which may be overlooked by laboratory routine genomic analyses (CMA and Whole Exome Sequencing) or only partially determined when associated with genomic losses at breakpoints. We finally introduce a possible role of SETBP1 in a Noonan-like phenotype.

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

Natural history in Malan syndrome: survey of 28 adults and literature review.

BACKGROUND: Malan syndrome (MALNS), previously referred to as "Sotos syndrome 2" due to its resemblance to Sotos syndrome (SS), is an ultra-rare neurodevelopmental disorder characterized by overgrowth, typical craniofacial features, intellectual disability (ID), and a range of psychobehavioral, musculoskeletal, vision and neurological signs. As MALNS and SS partly overlap, it is essential to more accurately profile their clinical presentations and highlight their differences in order to improve syndrome specific management. An increasing number of individuals with MALNS reach adult-age though the natural history of the disorder is poorly characterized due to the small number of adult individuals described so far. As a consequence, current guidelines are limited to the pediatric population. Further delineation of MALNS is essential to optimize care in adulthood. RESULTS: A mixed approach based on cross-sectional data collection with a survey disseminated to caregivers of adults with molecularly confirmed MALNS and literature review was conducted. Twenty-eight caregivers completed the survey. Clinical presentation in adulthood is multisystemic and defined by psychobehavioral comorbidities (96%), musculoskeletal involvement (96%), vision impairment (96%) and neurological complications (86%). The most common signs were anxiety (79%), hypotonia (75%), movement difficulty (75%), scoliosis (64%), problems with coordination (61%), strabismus (57%), constipation (54%), breastbone abnormalities (54%) and advanced bone age during childhood (54%). Impaired vision was complicated by vision decline (36%) and optic atrophy (32%). We report some previously unidentified features, including high pain threshold (46%), incontinence (25%), tremors (21%), muscle hypoplasia (18%) and tics (18%). CONCLUSIONS: This survey in the adult population has allowed a more complete description of the natural history of MALNS. Our findings will contribute to the development and improvement of standards of care for adults with MALNS to assure optimal health monitoring and treatment of evolutive complications. We propose additional recommendations to the previous dataset of clinical evaluations specifically applied to adults. The comparison of MALNS and SS adult presentation highlights significant differences in terms of prevalence and severity of ID, behavioral issues, and vision problems, confirming that a proper differential diagnosis between the two conditions is indispensable to guide physicians and mental health professionals to syndrome specific management.

2q24-q31 deletion: report of a case and review of the literature.

We report a patient with a de novo interstitial deletion of the long arm of chromosome 2 involving bands 2q24.3-q31.1. The patient shows postnatal growth retardation, microcephaly, ptosis, down-slanting palpebral fissures, long eyelashes and micrognathia. Halluces are long, broad and medially deviated, while the other toes are laterally deviated and remarkably short with hypoplastic phalanges. She also showed developmental delay, seizures, lack of eye contact, stereotypic and repetitive hand movements and sleep disturbances with breath holding. Prenatal and three independent postnatal karyotypes were normal. Array-CGH analysis allowed us to identify and characterize a "de novo" 2q interstitial deletion of about 10.4Mb, involving segment between cytogenetic bands 2q24.3 and 2q31.1. The deletion was confirmed by quantitative PCR. About 30 children with 2q interstitial deletion have been reported. The deletion described here is overlapping with 15 of these cases. We have attempted to compare the clinical features of our patient with 15 overlapping cases. The emerging phenotypes include low birth weight, postnatal growth retardation, mental retardation and developmental delay, microcephaly, and peculiar facial dysmorphisms. Peculiar long and broad halluces with an increased distance between the first and the second toe are ("sandal gap" sign) present in most of the described patients. The gene content analysis of the deleted region revealed the presence of some genes that may be indicated as good candidates in generating both neurological and dysmorphic phenotype in the patient. In particular, a cluster of SCNA genes is located within the deleted region and it is known that loss of function mutations in SCNA1 gene cause a severe form of epilepsy.

The physical map of the human RET proto-oncogene.

The RET proto-oncogene, a transmembrane tyrosine kinase receptor, is involved in the development of at least five different disease phenotypes. RET is activated through somatic rearrangements in a number of cases of papillary thyroid carcinoma while germ-line point mutations are associated with three inherited cancer syndromes MEN 2A, MEN 2B and FMTC. Moreover, point mutations or heterozygous deletions of RET are found in the dominant form of Hirschsprung disease or congenital colonic aganglionosis. We cloned the entire RET genomic sequence in a contig of cosmids encompassing 150 kb, from the CA repeat sTCL-2 to the region upstream the RET promoter, and established the position of the 20 exons of the RET gene with respect to a detailed restriction map based on eight endonucleases. A new highly polymorphic CA repeat sequence was identified within intron 5 of RET (RET-INT5). Finally the orientation of RET on chromosome 10q11.2 made it possible to orientate three other genes rearranged with RET in papillary thyroid carcinomas, namely H4/D10S170 on 10q21, R1 alpha on 17q23 and RFG2/Ele1 on 10q11.2.

Ectodermal dysplasias: a new clinical-genetic classification.

The ectodermal dysplasias (EDs) are a large and complex nosological group of diseases, first described by Thurnam in 1848. In the last 10 years more than 170 different pathological clinical conditions have been recognised and defined as EDs, all sharing in common anomalies of the hair, teeth, nails, and sweat glands. Many are associated with anomalies in other organs and systems and, in some conditions, with mental retardation.The anomalies affecting the epidermis and epidermal appendages are extremely variable and clinical overlap is present among the majority of EDs. Most EDs are defined by particular clinical signs (for example, eyelid adhesion in AEC syndrome, ectrodactyly in EEC). To date, few causative genes have been identified for these diseases. We recently reviewed genes known to be responsible for EDs in light of their molecular and biological function and proposed a new approach to EDs, integrating both molecular-genetic data and corresponding clinical findings. Based on our previous report, we now propose a clinical-genetic classification of EDs, expand it to other entities in which no causative genes have been identified based on the phenotype, and speculate on possible candidate genes suggested by associated "non-ectodermal" features.

Ectodermal abnormalities in Kabuki syndrome.

We describe a girl with Niikawa-Kuroki (Kabuki) syndrome (NKS) with conical incisors, hypodontia, hypoplastic nails, and brittle hair. Abnormal teeth are common in NKS and support a hypothesis of autosomal dominant inheritance of the syndrome [Halal et al., 1989; Silengo et al., 1996]. Hair abnormalities have never been investigated in NKS. The ectodermal involvement in NKS could represent an important clue for the understanding of the pathogenesis of this syndrome.

Fontaine-Farriaux craniosynostosis: second report in the literature.

Craniosynostosis is determined by the precocious fusion of one or more calvarial sutures leading to an abnormal skull shape. Additionally, nodular heterotopia is a disorder of neuronal migration and/or proliferation. We describe a very rare multiple congenital anomalies (MCA) syndrome in which craniosynostosis is associated with bilateral periventricular nodular heterotopia (BPNH) of the gray matter and other malformations involving hands, feet, and the gut. Clinical findings and further investigations suggest the diagnosis of craniosynostosis Fontaine-Farriaux type. To the best of our knowledge, this case is only the second report of this MCA syndrome. Based on the clinical and radiological data of the two cases reported, we hypothesize that this malformative complex may be considered a new BPNH/MCA syndrome and propose to classify it as BPNH/craniosynostosis. Previous studies demonstrated that at least two BPNH/MCA syndromes have been mapped to the Xq28 chromosomal region in which a causative gene for isolated BPNH is located. The same authors hypothesized that other BPNH syndromes could be due to microrearrangements at the same Xq28 region. Our case presents several overlapping features with some BPNH/MCA syndromes and it is possible that this new complex disorder may be caused by rearrangements at the same chromosomal region that could alter expression of different genes in Xq28.

Congenital hypoplastic anaemia in a patient with a new multiple congenital anomalies-mental retardation syndrome.

We report on a girl with congenital hypoplastic anaemia, "coarse" face, generalized hypertrichosis with scalp hypotrichosis, short fifth finger, hypoplastic toenails, and mental retardation. A sister of the proposita, who died at the age of 1 year, had severe congenital anaemia, hypoplastic fingernails, low birth weight, failure to thrive, and repeated upper respiratory tract infections. Based on family history, we suspect that hypoplastic anaemia and the same multiple congenital anomalies-mental retardation syndrome (MCA/MR) were also present in this sister. To the best of our knowledge, this patient represents the first report of congenital hypoplastic anaemia and such a complex MCA/MR syndrome, probably inherited as an autosomal recessive trait.

New clinical findings in oculo-ectodermal syndrome.

We report a 2-year-old male with aplasia cutis congenita of the scalp, epibulbar dermoids, strabismus and macrocephaly. In our opinion, he is affected by the Oculo-Ectodermal syndrome first described by Toriello et al. (1993). Am J Med Genet 45:764-766]. This is the sixth report of patients with this rare entity. Our case further expands the clinical spectrum of the syndrome to include mental retardation, seizures and microscopic hair changes.

Question mark ears, temporo-mandibular joint malformation and hypotonia: auriculo-condylar syndrome or a distinct entity?

We report a boy with prominent, peculiarly malformed ears, abnormality of the ramus of the mandible and hypotonia. An isolated peculiar bilateral ear deformity named 'question mark ear' has been delineated in plastic reconstruction surgery reviews [Cosman et al., 1970 Plast Reconstr Surg 46:454-457; Cosman (1984) Plast Reconstr Surg 73:572-576; Takato et al. (1989) Ann Plast Surg 22:69-73; Brodovsky (1997) Plast Reconstr Surg 100:1254-1257; Park (1998) Plast Reconstr Surg 101:1620-1623; Al-Quattan (1998) Plast Reconstr Surg 102:439-441] and a similar deformity of the ear and changes in the temporo-mandibular joint and condyle has been described by Jampol et al. [(1998) Am J Med Genet 75:449-452] and by Guion-Almeida et al. [(1999) Am J Med Genet 86:130-133]. The present case may be the third description of this malformation complex with additional clinical features characterized by hypotonia and mild developmental delay, or possibly a new distinct entity.

Ectodermal dysplasias: not only 'skin' deep.

The ectodermal dysplasias (EDs) are a large and complex nosologic group of diseases; more than 170 different pathologic clinical conditions have been identified. Despite the great number of EDs described so far, few causative genes have been identified. We review EDs in the light of the most recent molecular findings and propose a new classification of EDs integrating both molecular-genetic data and corresponding clinical findings of related diseases.

Sonographic and molecular diagnosis of thanatophoric dysplasia type I at 18 weeks of gestation.

Thanatophoric dysplasia is the most common type of lethal skeletal dysplasia. It can usually be diagnosed with ultrasound, but differential diagnosis with other osteochondrodysplasias is not always possible. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been demonstrated to cause two distinct subtypes of the disorder. We describe a case of thanatophoric dysplasia type I diagnosed at 18 weeks of gestation by ultrasonography. Genomic DNA obtained by chorionic villus sampling showed a C to G substitution at position 746 in the FGFR3 gene, resulting in a Ser249Cys substitution already known to be associated with type I disease. Implications for perinatal management are discussed.

Association of multiple endocrine neoplasia type 2 and Hirschsprung disease.

In a few patients with Hirschsprung disease (HSCR) and no clinical symptoms of multiple endocrine neoplasia type 2 (MEN-2A) or medullary thyroid carcinoma (MTC), missense mutations in the cysteine residues 609 and 620 of the Ret gene have been identified. In several pedigrees with either MEN-2A or familial MTC (FMTC) a documented germline mutation in cysteine 618 or 620 follows the segregation of the disease phenotype. The appearance of the HSCR phenotype in such patients and pedigrees cannot be easily reconciled with the gain of function which is associated with the dominant oncogenic effect of MEN-2A mutations. Gastrointestinal manifestations are known to occur also in association with MEN-2B but, to the best of our knowledge, in only very few cases the intestinal phenotype of MEN-2B has been investigated by enzymo-histochemical techniques, as in the present work. We report an extensive molecular study of patients, two with HSCR and FMTC carrying a Cys620Arg or Ser mutation and two with MEN-2B and gastrointestinal symptoms carrying a Met918Thr mutation. One of the latter two patients showed aganglionosis of the last 5 cm of rectum which caused a congenital megacolon leading to the diagnosis and operation for HSCR. The mutation screening of all the exons of Ret in 3 of these patients did not reveal any additional mutation. Therefore these results do not support the hypothesis of additional constitutional Ret mutations in patients showing association of MEN-2 and HSCR, whilst the histochemical and clinical data in one of these patients indicate that MEN-2B can be associated with a true form of short segment HSCR.

Exclusion of the Sonic Hedgehog gene as responsible for Currarino syndrome and anorectal malformations with sacral hypodevelopment.

Anorectal malformations (ARMs) are common congenital anomalies that account for 1:4 digestive malformations. ARM patients show different degrees of sacral hypodevelopment while the hemisacrum is characteristic of the Currarino syndrome (CS). Cases of CS present an association of ARM, hemisacrum and presacral mass. A gene responsible for CS has recently been mapped in 7q36. Among the genes localized in this critical region, sonic hedgehog (SHH) was thought to represent a candidate gene for CS as well as for ARM with different levels of sacral hypodevelopment according to its role in the differentiation of midline mesoderm. By linkage analysis we confirmed the critical region in one large family with recurrence of CS. In addition, the screening of SHH in 7 CS and in 15 sporadic ARM patients with sacral hypodevelopment allowed us to exclude its role in the pathogenesis of these disorders.