A Verloes

Molecular analysis of pericentrin gene ( PCNT ) in a series of 24 Seckel/microcephalic osteodysplastic primordial dwarfism type II (MOPD II) families

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II, MIM 210720) and Seckel syndrome (SCKL, MIM 210600) belong to the primordial dwarfism group characterised by intrauterine growth retardation, severe proportionate short stature, and pronounced microcephaly. MOPD II is distinct from SCKL by more severe growth retardation, radiological abnormalities, and absent or mild mental retardation. Seckel syndrome is associated with defective ATR dependent DNA damage signalling. In 2008, loss-of-function mutations in the pericentrin gene (PCNT) have been identified in 28 patients, including 3 SCKL and 25 MOPDII cases. This gene encodes a centrosomal protein which plays a key role in the organisation of mitotic spindles. The aim of this study was to analyse PCNT in a large series of SCKL-MOPD II cases to further define the clinical spectrum associated with PCNT mutations. Among 18 consanguineous families (13 SCKL and 5 MOPDII) and 6 isolated cases (3 SCKL and 3 MOPD II), 13 distinct mutations were identified in 5/16 SCKL and 8/8 MOPDII including five stop mutations, five frameshift mutations, two splice site mutations, and one apparent missense mutation affecting the last base of exon 19. Moreover, we demonstrated that this latter mutation leads to an abnormal splicing with a predicted premature termination of translation. The clinical analysis of the 5 SCKL cases with PCNT mutations showed that they all presented minor skeletal changes and clinical features compatible with MOPDII diagnosis. It is therefore concluded that, despite variable severity, MOPDII is a genetically homogeneous condition due to loss-of-function of pericentrin.

Holoprosencephaly-polydactyly ('pseudotrisomy 13') syndrome: a syndrome with features of hydrolethalus and Smith-Lemli-Opitz syndromes. A collaborative multicentre study.

A syndrome of holoprosencephaly and postaxial polydactyly, associated with hydrocephalus, heart defect, adrenal hypoplasia, and other visceral malformations, has been observed in five unrelated children with normal chromosomes. Clinical overlap with lethal acrodysgenital dwarfism (Smith-Lemli-Opitz syndrome type II) and hydrolethalus syndrome is discussed. Recessive inheritance seems likely.

Recessive metaphyseal dysplasia without hypotrichosis. A syndrome clinically distinct from McKusick cartilage-hair hypoplasia.

Among children with recessive metaphyseal dysplasia involving the knees and extremities, two types can be distinguished. In true cartilage-hair hypoplasia, as described by McKusick, many patients show clinical hair involvement and variable immunodeficiency. We present a series of six patients with the same radiological changes, but without apparent hypotrichosis. We suggest that they should be considered as having a variant form of cartilage-hair hypoplasia, with a clinically distinct phenotype, which could be as common as true cartilage-hair hypoplasia among non-Amish populations. Microscopic examination of the hair may show reduction in the diameter of the hair shaft. This form of metaphyseal dysplasia may result from allelic heterogeneity.

The orocraniodigital syndrome of Juberg and Hayward.

We report three new isolated cases of orocraniodigital syndrome (Juberg-Hayward syndrome). The main clinical features of this unusual birth defect (six patients from three families described so far) are cleft lip/palate, hypertelorism, bowed and upward slanting eyebrows, thumb hypo/aplasia or proximal/distal thumb displacement, luxation of the radial head, elbow restriction, minor vertebral and rib anomalies, and horseshoe kidneys. New features observed in our patients are severe mental impairment (not correlated with the severity of the malformations), anterior anal displacement, and ptosis. Recessive inheritance is likely, but autosomal dominant inheritance cannot yet be totally ruled out; therefore, genetic counselling of parents of an affected child and of affected patients themselves must be cautious.

WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.

Prenatal findings in cardio-facio-cutaneous syndrome

Our study was designed to analyze prenatal manifestations in patients affected with cardio‐facio‐cutaneous syndrome (CFCS), in order to define indications of DNA testing in utero. Prenatal features were extracted from a national database and additional data were collected from 16 families contacted through the French association of CFC‐Costello syndrome. We collected results of ultrasound scan (USS) biometrics, presence of congenital birth defects, and polyhydramnios. From the database, increased nuchal translucency was present in 13% of pregnancies, polyhydramnios in 52%, macrosomia and/or macrocephaly in 16%. Of the 16 pregnancies, 81% were complicated by abnormal USS findings. Polyhydramnios was reported in 67%. Head circumference, biparietal diameter, and abdominal circumference were above the 90th centile in 72%, 83% and, 81% of fetuses, respectively. Contrasting with macrosomia, femur length was below the 10th centile in 38%. Urinary tract abnormalities were found in 47% of fetuses. Most CFCS fetuses showed a combination of macrocephaly, macrosomia, and polyhydramnios, contrasting with relatively short femora. This growth pattern is also seen in Costello syndrome. We suggest that screening for CFCS and Costello gene mutations could be proposed in pregnancies showing this unusual pattern of growth parameters.

Failure of ossification of the occipital bone in mandibuloacral dysplasia type B.

Mandibuloacral dysplasia with type B lipodystrophy is a rare autosomal recessive disease characterized by atrophic skin, lipodystrophy, and skeletal features. It is caused by mutations in ZMPSTE24, a gene encoding a zinc metalloproteinase involved in the post‐translational modification of lamin. Nine distinct pathogenic variants have been identified in 11 patients from nine unrelated families with this disorder. We report a 12‐year‐old boy with mandibuloacral dysplasia with type B lipodystrophy and a novel homozygous c.1196A>G; p.(Tyr399Cys) mutation in ZMPSTE24. The patient had typical dermatological and skeletal features of mandibuloacral dysplasia with type B lipodystrophy, sparse hair, short stature, mild microcephaly, facial dysmorphism, and a striking failure of ossification of the interparietal region of the occipital bone, up to the position where transverse occipital suture can be observed. Newly recognized signs for mandibuloacral dysplasia with type B lipodystrophy were gaze palsy and ptosis. Delayed closure of cranial sutures and Wormian bones have been described in three patients, but an ossification failure strictly limited to the occipital bone, as seen in the present patient, appears to be unique for mandibuloacral dysplasia with type B lipodystrophy. This observation illustrates that ZMPSTE24 could play a specific role in membranous ossification in the interparietal part of the squama (Inca bone) but not in the intracartilaginous ossification of the supraoccipital. This failure of ossification in the squama appears to be a useful feature for the radiological diagnosis of mandibuloacral dysplasia with type B lipodystrophy.

A de novo 17q21.2 duplication in a boy with developmental delay and dysmorphic features.

We report a boy with severe developmental delay, microcephaly and characteristic facial dysmorphism consisting in round face, hypertelorism, upslanted palpebral fissures, small nose, large mouth, micrognathia, sparse hair and eyelashes. Array-CGH revealed a de novo duplication of 103xa0kb within 17q21.2 not reported to date. The duplication includes 8 genes: DHX58, KAT2A, HSPB9, RAB5C, KCNH4, HCRT, GHDC and STAT5B. Three genes (KATA2, KCNH4, and STAT5B) may contribute to intellectual deficiency. Further observations will be necessary to confirm the specificity of the facial Gestalt.