Fraser-cryptophthalmos syndrome with colonic atresia

Fraser cryptophthalmos syndrome is a severe genetic disorder comprising of cryptophthalmos, syndactyly and genitourinary abnormalities. Gastrointestinal malformations are also increasingly being described. We describe a neonate with this syndrome having colonic atresia leading to cecal rupture and pneumoperitoneum.     

Cryptophthalmos

Cryptophthalmos, a very rare congenital anomaly of the eye, is characterised by skin passing continuously from the forehead to the cheek over a malformed eye. It may be isolated or more commonly as a part of Fraser syndrome. Cryptophthalmos is classified into three types: complete, incomplete and abortive. Surgical reconstruction is the modality of treatment available. We present a case of bilateral, complete, isolated cryptophthalmos, who has undergone stage 1 of reconstructive surgery.     

Fraser syndrome: a new case report with review of the literature

Fraser syndrome is an autosomal recessive disorder characterized by cryptophthalmos and cutaneous syndactyly. We present a case of Fraser syndrome with bilateral cryptophthalmos and other common features of Fraser syndrome including syndactyly (hands and feet bilaterally), ambiguous genitalia with clitoromegaly, vaginal atresia, and unilateral renal agenesis. We also present the major and minor diagnostic criteria for Fraser syndrome and the frequency of associated malformations.     

Abortive cryptophthalmos: a case report and a review of cryptophthalmos

Cryptophthalmos is a rare, probably autosomal recessive condition in which the lid folds fail to separate in the embryo resulting in a continuous sheet of skin from the forehead to the cheeks covering the eyes. Cryptophthalmos has many variants and is usually associated with multiple other congenital anomalies. This article reports on an isolated case of "abortive cryptophthalmos" with multiple systemic anomalies. The surgical treatment is described and the general features of the cryptophthalmos syndrome and its variants are reviewed.     

Evidence for decreased growth hormone in patients with hypothalamic hamartoma due to Pallister-Hall syndrome

Pallister-Hall syndrome (PHS) is characterized by hypothalamic hamartoma, bifid epiglottis, and central or postaxial polydactyly. Familial transmission is autosomal dominant; isolated cases also occur. To screen for hypothalamic-pituitary dysfunction in PHS, we studied a 12 year-old boy (patient #1), and 14 additional patients (patients #2-14: 7M, 7F; ages 4-72 yr). We performed serial sampling of GH, LH/FSH, TSH, and cortisol from 20.00-08 00 h. At 08.00 h, we measured IGF-I, peak responses of LH and FSH after GnRH, and cortisol after ACTH. We found that 6/7 children, including patient #1, and 6/8 adults had low or absent spontaneous GH secretion and/or low levels of IGF-I. Patient #1 also had accelerated pubertal development, but no other patient had abnormalities of the pituitary-gonadal axis, and none of the 14 patients had an abnormal thyroid or adrenal axis. We conclude that decreased pituitary GH secretion is common in PHS, and may exist in the absence of other forms of endocrine dysfunction.     

Hypertrichosis cubiti (hairy elbow syndrome): a clue to a malformation syndrome

Hypertrichosis cubiti (HC) or hairy elbow syndrome (OMIM # 139600) consists of a localised form of long vellus hair on the extensor surfaces of the distal third of the upper arm and the proximal third of the forearm bilaterally, or occasionally on other parts of the body. In the 28 cases reported in the literature so far the elbow hair abnormality was either isolated or associated with short stature or other physical abnormalities. Most of these cases were sporadic, but autosomal dominant as well as autosomal recessive inheritance patterns have been postulated. We report on three unrelated girls (aged 7 to 11 years) of whom one presented with excess hair in the elbows alone and the other two had associated abnormalities including short stature, dysmorphic facial features and mental retardation. The literature on this subject has been reviewed and the authors focus on cases of HC with associated anomalies. A pathogenic explanation by somatic mosaicism is proposed.     

Clinical and pathological aspects of ARC (arthrogryposis, renal dysfunction and cholestasis) syndrome in two siblings

We describe the first family report of ARC syndrome (arthrogryposis multiplex congenita, renal dysfunction, and cholestasis) diagnosed in Turkey. ARC syndrome is a rare cause of cholestatic jaundice and skeletal abnormalities in the neonatal period. Fanconi-like renal tubular dysfunction completed the clinical picture. Consanguinity and affected membership are the other typical components of this rare disorder, and possibility of autosomal recessive transmission was considered. A broad spectrum of histopathological abnormalities have been described in the liver and kidney. In this report, we describe two male siblings with ARC syndrome who had cholestatic jaundice, arthrogryposis multiplex congenital-like joint contractures and renal involvement with additional clinical features. Clinical and pathological aspects of the syndrome are discussed and compared with the other cases in the literature.     

Kidney transplantation in a child with Pierson syndrome

Congenital nephrotic syndrome is commonly associated with mutations in genes that encode podocyte and slit diaphragm proteins or the structural and regulatory proteins of the GBM. These mutations lead to the formation of dysfunctional proteins, which account for the resistance of the renal manifestations to conventional treatment methods. Consequently, patients become renal replacement therapy dependent. Mutation of the LAMB2 gene is associated with Pierson syndrome, which is an autosomal recessive disorder characterized by congenital nephrotic syndrome and ocular abnormalities. In this report, a 2‐year‐old male patient who was diagnosed with Pierson syndrome is presented. He had bilateral microcoria and developmental delay in addition to nephrotic syndrome. His renal function deteriorated rapidly, and he underwent a deceased donor kidney transplantation. He showed dramatic improvement after kidney transplantation; in addition to having good renal function, he started to catch up to his peers in terms of growth. Pierson syndrome should be considered during the diagnostic investigations of children with renal manifestations and ocular abnormalities. Children with Pierson syndrome must be evaluated in terms of kidney transplantation as soon as they are diagnosed.     

The Antley-Bixler syndrome: Report of two familial cases with severe renal and anal anomalies

The Antley-Bixler syndrome is characterized by premature closure of coronal and lambdoidal sutures, proptosis, depression of the nasal bridge, brachycephaly, radio-humeral synostosis and bowing of ulnae and femora associated with fractures. Most cases have been reported after birth with only one case diagnosed prenatally after recurrence of this autosomal recessive syndrome. The two present cases are of interest because of prenatal diagnosis of renal agenesis in the first case and early detection of clinical signs during the second pregnancy. Beside the unusual severity of the renal abnormalities, both cases had an imperforate anus in addition to the more common genital abnormalities.     

Prenatal death in Fraser syndrome

Cryptophthalmos may be partial or complete, unilateral or bilateral, apparently nonsyndromal or syndromal. A recent study of 2 stillborn infants at the University of Utah prompted an analysis of the developmental aspects of the syndromal form (Fraser syndrome). We conclude that, per se, cryptophthalmos is a developmental field defect on the basis of heterogeneity (autosomal dominant and recessive forms) and phylogeneity (occurrence also in the pheasant, rabbit, pigeon, dog, and mouse). In humans this autosomal recessive disorder maps to 4q21, is homologous to the bleb (bl/bl) mouse, and is due to mutations in the FRAS1 gene that codes for a 4007 amino acid protein 85% identical to the Fras1 gene of the bleb mouse. Commonest anomalies in humans are cryptophthalmos, cutaneous syndactyly of digits, abnormal ears and genitalia, renal agenesis, and congenital heart defects. Almost half of affected infants are stillborn or die in infancy, and mental retardation is common. The pathogenesis evidently involves abnormal epithelial integrity during prenatal life. Older (mostly German) publications, some dating to the 19th century, provide a fascinating historical insight into the process of syndrome delineation.     

Cervico-oculo-acusticus (Wildervanck's) syndrome: a clinical variant of Klippel-Feil sequence?

A 7-year-old female child with phenotype of Cervico-Oculo-Acousticus (Wildervanck's) syndrome is presented. In addition to fusion of multiple cervical vertebrae with short neck, abducens nerve palsy and deafness, the child showed severe growth and bone delay, renal abnormalities and slight mental retardation. The presence of such malformations seems to suggest that Wildervanck's syndrome is a clinical variant of Klippel-Feil sequence. Both conditions usually have sporadic occurrence with female prevalence, more consistent for cervico-oculo-acousticus syndrome. The possibility of dominant inheritance has been postulated for both, autosomal for Klippel-Feil, autosomal or X-linked with lethality in hemizygous for Wildervank's one. An environmental etiology, due to a vascular disruption sequence during embryonic development, has been noted in Klippel-Feil, as in Moebius and Poland sequences. A combination of defects (Klippel-Feil and Moebius) could induce the more complex phenotype observed in Wildervanck's syndrome.     

Growth hormone deficiency in patients with 22q11.2 deletion: expanding the phenotype

The list of findings associated with the 22q11.2 deletion is quite long and varies from patient to patient. The hallmark features include: conoruncal cardiac anomalies, palatal defects, thymic aplasia or hypoplasia, T cell abnormalities, mild facial dysmorphia, and learning disabilities. The 22q11.2 deletion has been seen in association with the DiGeorge sequence, velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome, isolated conotruncal cardiac anomalies, and some cases of autosomal dominant Optiz G/BBB syndrome. Short stature has been seen in one to two thirds of children reported in the literature with a diagnosis of VCFS, but growth hormone deficiency (GHD) has not been described in conjunction with this diagnosis. We present 4 patients with a 22q11.2 deletion and short stature who were found to have abnormalities in the growth hormone-insulin-like growth factor I axis. All had growth factors less than -2 SD for age and failed provocative growth hormone testing. Two patients were found to have abnormal pituitary anatomy. In our population, the incidence of GHD in 4 or 95 children with 22q11 deletion is significantly greater than the estimated incidence of GHD in the general population. Children with a 22q11.2 deletion appear to be at a greater risk for pituitary abnormalities. Therefore, those children with the 22q11.2 deletion and short stature or poor growth should be evaluated for GHD, as replacement growth hormone therapy may improve their growth velocity and final height prediction.     

Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases

We have observed two types of paucity of interlobular bile ducts (PILBD) in children with chronic cholestasis: the syndromic type, which is more frequent (80 cases), and the nonsyndromic type (31 cases). Study of patients with syndromic PILBD has enabled us to recognize five major features: peculiar facies (95%), chronic cholestasis (91%), posterior embryotoxon (88%), butterfly-like vertebral arch defects (87%), and peripheral pulmonary artery hypoplasia or stenosis, either isolated or associated with complex cardiovascular abnormalities (85%). By observing these major features, it is possible to differentiate the "complete" syndrome, in which all five features are present (26 cases), from the "partial" syndrome, in which only four (42 cases) or three (12 cases) major features are present. Other less frequent features were observed in patients with complete or partial syndrome: growth retardation (50%), mental retardation (16%), renal disturbances, other vascular malformations, bone abnormalities, high-pitched voice, and delayed puberty. Death occurred in 21 (26%) patients with syndromic PILBD. Therapy consisted of supplementation of medium-chain triglycerides and fat-soluble vitamins and administration of cholestyramine or phenobarbital. An autosomal dominant mode of transmission, with variable penetrance, seems likely.     

Two sisters with Bardet-Biedl syndrome: brain abnormalities and unusual facial findings

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with a wide spectrum of clinical manifestations. BBS is predominantly characterized by dysmorphic distal extremities, obesity, structural abnormalities or functional impairment of the kidney, rod cone dystrophy, and varying degrees of mental retardation. Hypogenitalism is also present, only in males, and in all cases, facial similarities. We present herein two sisters with BBS, one of whom also had cerebellar vermis hypoplasia and cerebral and cerebellar atrophy, and both of whom had ocular abnormalities in the form of epicanthus and telecanthus and metabolic syndrome. It should also be emphasized that the occurrence of cerebellar involvement such as cerebellar vermis hypoplasia and cerebellar atrophy in BBS is very unusual. The association of abnormalities in brain development and other facial features in children with BBS is not seen frequently; thus, these abnormalities should be searched carefully.     

Elastin Mutation Screening in a Group of Patients Affected by Vascular Abnormalities

Supravalvular aortic stenosis is an uncommon but well-characterized congenital form of left ventricular outflow obstruction. The lesion involves the ascending aorta and often occurs in association with pulmonary arterial stenoses or stenoses of other arteries, especially at major branch points. It can occur sporadically, as an autosomal dominant condition, or as one component of Williams-Beuren syndrome. In fact, the clinical and structural characteristics of supravalvular aortic stenosis are identical in both syndromic and nonsyndromic cases. The severity of supravalvular aortic stenosis varies; but if it is left untreated, it may result in heart failure, myocardial infarction, and sudden death. Supravalvular aortic stenosis in Williams-Beuren patients occurs as a consequence of a complete deletion of one copy of the elastin gene on chromosome 7q11.23. However, the underlying genetic cause of isolated supravalvular aortic stenosis has been identified as translations, gross intragenic deletions, and point mutations that disrupt the elastin gene. We report the results obtained in a mutation screening of the elastin gene in 28 patients with supravalvular aortic stenosis and other vascular abnormalities. The aim of the screening was to characterize the molecular cause of this lesion. We have detected 11 changes, including nine polymorphisms and two novel putative missense mutations. Grant support: 98TV1110 from “Fundació Marató TVS”, and V2003RedC-07 from “Institute de salud Carlos III”.     

PHACE syndrome: new views on diagnostic criteria.

The association of large facial hemangiomas with posterior fossa malformations and vascular anomalies has been termed the PHACE syndrome. It is characterized by the association of posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and other cardiac defects, and eye abnormalities. Since most articles focus on isolated case reports, an extended retrospective literature review of all reports of large hemangiomas with associated abnormalities of the central nervous system and other malformations was performed to examine the clinical features, and other not as yet reported associated anomalies. Reports were found on 59 patients with PHACE syndrome, to which we added ten cases of our own. The Dandy-Walker syndrome is the most common CNS abnormality reported in association with PHACE syndrome and was seen in 48 (81 %) patients. Arterial malformations were found in 13 (22 %) cases; only 11 patients (19 %) had structural arterial abnormalities without associated Dandy-Walker complex. As published, about one third of patients (31 %) had further ophthalmologic abnormalities, and cardiac anomalies, including coarctation of the aorta. Subglottic hemangiomas were seen in 4 (7 %) patients and ventral developmental defects also in 3 cases. In seven of 59 patients (12 %) with PHACE syndrome, intracranial hemangiomas were present. This study demonstrates that among other CNS abnormalities, special attention should be given to intracranial hemangiomas which seems to be a peculiar phenotype of PHACE syndrome. We therefore suggest that a sixth criterion should be added to the five minimal inclusion criteria for PHACE syndrome. The inclusion criteria would then be: arterial abnormalities or/and intracranial hemangiomas. On the basis of our experience with our patients and with those previously reported, we stress the importance of using contrast-enhanced imaging to detect intracranial lesions.     

Unusual dysmorphic features in five patients with Noonan's syndrome: a brief review

Noonan's syndrome is a relatively common, multiple congenital anomaly syndrome, genetically inherited as an autosomal dominant disorder with variable penetrance. It is defined by a characteristic phenotype, congenital heart disease, ocular defects and mild mental retardation. Molecular studies have confirmed that it is a heterogeneous disorder and there may be evidence for an autosomal recessive mode of inheritance.1 The gene responsible for Noonan' syndrome has been mapped to the long arm of chromosome 12.2,3 The human deltex gene (DLT x 1), mapping to chromosomal region 12q24 in the vicinity of the Noonan's syndrome critical region is being evaluated as a candidate gene for this disorder.4 Various types of musculoskeletal abnormalities have been reported, including short stature, craniofacial dysmorphism, short or webbed neck and fetal pads in fingers and toes.5 We report five cases with the unusual physical features of overriding toes and simian creases. Such abnormalities can be considered among the minor manifestations of the syndrome.     

Association Between Graves’ Disease and Renal Coloboma Syndrome: A Case Report

Renal coloboma syndrome is an autosomal dominant condition characterized by renal lesions and optic nerve abnormalities. We report an 11-yr-old Japanese girl with familial renal coloboma syndrome, who also had Graves’ disease. Four affected family members had a previously reported heterozygous mutation (c.76dupG, p.Val26Glyfs*28) in the PAX2 gene. We hypothesized that PAX2 mutations may increase the risk of autoimmune diseases through alterations of human β-defensin 1 expression.     

Early onset lymphoedema,recessive form — a new form of genetic lymphoedema syndrome

We report on two brothers with chronic congenital lymphoedema. Besides the oedemas of limbs we found an unusual facial appearance, abnormalities of external genitals as a deformation sequence resulting from intrauterine oedemas and intestinal lymphoedema. This X-linked or autosomal recessive trait may be a new entity, to be differentiated from other genetic lymphoedema syndromes, the so-called familial protein-losing enteropathy, and dominantly inherited intestinal lymphangiectasia. A prominent sign of the syndrome is chemosis and injection of conjunctiva.