Recent Advances in Craniosynostosis.

Craniosynostosis is a pathologic craniofacial disorder and is defined as the premature fusion of one or more cranial (calvarial) sutures. Cranial sutures are fibrous joints consisting of nonossified mesenchymal cells that play an important role in the development of healthy craniofacial skeletons. Early fusion of these sutures results in incomplete brain development that may lead to complications of several severe medical conditions including seizures, brain damage, mental delay, complex deformities, strabismus, and visual and breathing problems. As a congenital disease, craniosynostosis has a heterogeneous origin that can be affected by genetic and epigenetic alterations, teratogens, and environmental factors and make the syndrome highly complex. To date, approximately 200 syndromes have been linked to craniosynostosis. In addition to being part of a syndrome, craniosynostosis can be nonsyndromic, formed without any additional anomalies. More than 50 nuclear genes that relate to craniosynostosis have been identified. Besides genetic factors, epigenetic factors like microRNAs and mechanical forces also play important roles in suture fusion. As craniosynostosis is a multifactorial disorder, evaluating the craniosynostosis syndrome requires and depends on all the information obtained from clinical findings, genetic analysis, epigenetic or environmental factors, or gene modulators. In this review, we will focus on embryologic and genetic studies, as well as epigenetic and environmental studies. We will discuss published studies and correlate the findings with unknown aspects of craniofacial disorders.

Neutrophil oxidative metabolism in Down syndrome patients with congenital heart defects.

Down syndrome (DS) occurs when an individual has three, rather than two, copies of the 21st chromosome. Cytosolic superoxide dismutase (SOD-1) is encoded by a gene on chromosome 21 and thus, SOD-1 activity is elevated in patients with DS. Forty percent of all cases with DS are associated with congenital heart defects (CHD). Although the contribution of SOD1 to disease phenotype is unknown, it is considered to be a "molecular marker" of the disease. It was hypothesized herein that the presence of CHD may alter the expression of SOD1 and oxidative metabolism in patients with DS. This hypothesis was tested via four experimental groups as follows: patients with DS without CHD, DS patients with CHD, CHD patients without DS and controls. Expression and activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), myeloperoxidase (MPO), and catalase (CAT) were determined in neutrophils from all experimental groups. Intracellular hydrogen peroxide concentration and superoxide release were also evaluated in neutrophils. A significant increase was observed in SOD and GPx amount and activity in patients with DS with and without CHD. No significant difference was found in the amount and activity of MPO and CAT among the different experimental groups. Intracellular hydrogen peroxide concentration was similar in all groups, whereas a prominent decrease was seen in superoxide release in cases with DS. Patients with DS with and without CHD showed no significant differences in any of the measured parameters. The data suggest that CHD observed in patients with DS does not result from altered redox metabolism associated with the disease.

Subtelomeric rearrangements of dysmorphic children with idiopathic mental retardation reveal 8 different chromosomal anomalies.

Subtelomeric rearrangements are an important cause of both sporadic and familial idiopathic mental retardation (MR) and/or congenital malformation syndromes. We report on a cohort of 107 children with idiopathic MR and normal karyotype 450-550 band level by GTG banding screened for subtelomeric rearrangements by multiprobe fluorescence in situ hybridization (FISH). In these cases, five patients had de novo deletions (1p deletion was found in 2 cases; 3q deletion, 9p and 9q deletions were found in 1 case each) and four patients had unbalanced rearrangements [der(5)t(5;15)(pter;qter)pat in 2 patients who were siblings, rec(10)dup(10p)inv(10)(p13q26)mat in 1 patient and der(18)t(18;22)(qter;qter) de novo in 1 patient]. Our study confirms that the subtelomeric rearrangements are a significant cause of idiopathic MR with dysmorphic features.

Aplasia cutis congenita: three cases with three different underlying etiologies.

Aplasia cutis congenita (ACC) is an uncommon condition in which localized or widespread areas of skin are absent or scarred at birth. There is no single underlying cause of ACC, as it simply represents a physical finding that reflects a disruption of intrauterine skin development. Here we report three cases of ACC of the scalp with three different etiologies: congenital rubella syndrome, trisomy 13 and fetal valproate syndrome. The aim of the present report is to increase awareness of these skin defects and emphasize the importance of underlying etiologies.

Oral-facial digital syndrome type 1.

The oral-facial-digital syndrome type 1 is characterized by following abnormalities: pseudocleft of the upper lip, tongue lobulation, hamartomata on the tongue, alveolar frenulae, and clefting of the soft palate. We report a 9-month-old girl who was referred to our clinic due to facial dysmorphology in addition to cleft palate and multiple masses on the tongue which resulted in feeding problems. Surgical intervention was done. Molecular analysis revealed absence of OFD gene.

Maternal origin and clinical findings in a case with trisomy 22.

We report a newborn girl with multiple congenital anomalies whose chromosomal analysis showed complete trisomy 22. Her phenotype included microcephaly, epicanthus, hypertelorism, micrognathia, cleft palate, microtia, and preauricular tag. She died in the 24th post-natal hour. Trisomy 22 was shown by fluorescence in situ hybridization technique and the parental origin of the extra chromosome was found to be maternal by DNA microsatellite marker analysis of chromosome 22. Postmortem examination revealed the presence of atrioseptal defect and stasis in the biliary canals. We believe that this patient will contribute to the literature both by clinical findings and short life span associated with maternal origin of extra chromosome 22.

PHACES syndrome presenting as hemangiomas, sternal clefting and congenital ulcerations on the helices.

Sternal malformation/vascular dysplasia association is a very rare condition comprised of midline defects and hemangiomas of the face and anterior trunk, that can be found as part of the PHACES phenotypic spectrum (posterior fossa malformations, hemangiomas, arterial anomalies, coarctations of the aorta, cardiac defects and eye abnormalities, sternal clefting). Herein, we describe a 6-month-old boy with sternal cleft, extensive segmental hemangiomas, and a depigmented scar on the tip of the xyphoid process, corresponding to a sternal malformation/vascular dysplasia association. He also had bilateral cutaneous ulcerations on the helices. Our case report indicates that ulceration of a hemangioma can occur before significant proliferation and may even be present congenitally.

Evaluation of a fetus with Neu-Laxova syndrome through prenatal, clinical, and pathological findings.

We report a case of Neu-Laxova syndrome in a fetus at 22 weeks with the ultrasonographic findings of characteristic facial findings, limb contractures, kyphosis and polyhydramnios. Pathological and ultrasonographic studies are discussed.

A case of Costello with parathyroid adenoma and hyperprolactinemia.

A 23-year-old female with Costello syndrome is presented. She had mental retardation, macrocephalia, "coarse" facial features, deep palmar and plantar creases, hyperkeratosis in palms and soles, hyperpigmentation, curly hair, and cutis laxa, which are among the diagnostic features of the syndrome, and a history of hyperprolactinemia since the age of 16. Her present complaint was weakness and widespread bone-pain. In routine biochemistry, she had an elevated calcium level of 11.1 (8.6-10.2) mg/dl and her DEXA evaluation was consistent with osteoporosis (vertebra and femur T score <-2.5). High PTH levels, 103 (8-78) pg/ml, suggested presence of a parathyroid adenoma. Tc-MIBI scintigraphy revealed two focuses of pathological uptake, one located inferior to left lobe of thyroid and the other in the superior left lobe of thyroid gland. After parathyroid adenomectomy, her serum calcium and PTH levels returned to normal values. This is the first case of parathyroid adenoma and hyperprolactinemia in the literature, reported in a patient with Costello syndrome.