Congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly: Cantú syndrome.

Cantú syndrome (hypertrichosis, osteochondrodysplasia, cardiomegaly) is a rare condition, previously reported in 13 patients. We report on two additional patients with this disorder. One of the patients had pulmonary hypertension of unknown cause which was responsive to steroid therapy. She also had unusual, deep plantar creases, not reported previously in Cantú syndrome. Autosomal recessive inheritance has been suggested previously on the basis of sib recurrence in one family and consanguinity in another. We have performed a segregation analysis based on all reported families to date; the data indicate autosomal recessive inheritance is unlikely. A new dominant mutation or microdeletion syndrome are more likely possibilities, sib recurrence possibly representing gonadal mosaicism.     

Autosomal dominant inheritance in Cantú syndrome (congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly)

Cantú syndrome (CS) is characterized by congenital hypertrichosis, osteochondrodysplasia, cardiomegaly, and coarse facial appearance; autosomal recessive inheritance has been postulated. We report on a Mexican family with CS; the affected members are the 44-year-old father and his two children (a male and female), aged 14 and 4 years, respectively; each shows the classic characteristics, but the father and the brother also have a previously unreported feature, namely, a thick calvarium. This is the first reported instance of male-to-male transmission of CS. With the paternal age effect found in the reported sporadic cases and the segregation analysis [Robertson et al., 1999], autosomal dominant inheritance is more likely than autosomal recessive inheritance. The cases of affected sibs reported by Cantú et al. [1982] could be explained by parental gonadal mosaicism.     

Cantú syndrome: report of nine new cases and expansion of the clinical phenotype

Cantú syndrome, a rare disorder of congenital hypertrichosis, characteristic facial anomalies, cardiomegaly, and osteochondrodysplasia was first described in 1982 by Cantú. Twenty-three cases of Cantú syndrome have been reported to date. The pathogenesis of this rare autosomal dominant condition is unknown. We describe 10 patients with Cantú syndrome (9 new cases and the long-term follow-up of a 10th case reported by Robertson in 1999) comparing the phenotype with that of the previously reported cases. We describe how the distinctive facial appearance evolves with time and report several new findings including recurrent infections with low immunoglobulin levels and gastric bleeding in some of our patients. The cardiac manifestations include patent ductus arteriosus, septal hypertrophy, pulmonary hypertension, and pericardial effusions. They may follow a benign course, but of the 10 cases we report, 4 patients required surgical closure of the patent ductus arteriosus and 1 patient a pericardectomy. Long-term follow-up of these patients has shown reassuring neuro-developmental outcome and the emergence of a behavior phenotype including obsessive traits and anxiety.     

Further case of Cantú syndrome: exclusion of cryptic subtelomeric chromosome aberrations

Cantú syndrome consists of hypertrichosis, osteochondrodysplasia, and cardiomegaly, and has been reported in 18 patients to date. We report an infant with Cantú syndrome. In addition to typical findings, he had relatively mild radiological and cardiological manifestations. Previously undescribed findings included pyloric stenosis and elevated alkaline phosphatase levels. Brain scans showed bilateral calcification of the Arteriae thalamostriatae and widening of the outer liquor spaces and lateral ventricles. Because the propositus is the youngest patient reported to date, our findings refine the clinical spectrum of Cantú syndrome in neonates and young infants. The etiology and mode of inheritance of Cantú syndrome are unknown. Most cases are sporadic. Microdeletions have been discussed as a possible cause of Cantú syndrome. Recently, several syndromes with multiple congenital anomalies and mental retardation have been shown to be caused by subtelomeric chromosome aberrations. We excluded the presence of a cryptic subtelomeric chromosome anomaly in our patient by fluorescence in situ hybridization (FISH) screening with locus-specific probes.     

Cantú syndrome versus Zimmermann-Laband syndrome: Report of nine individuals with ABCC9 variants

Cantú syndrome (CS) is a rare developmental disorder characterized by a coarse facial appearance, macrocephaly, hypertrichosis, skeletal and cardiovascular anomalies and caused by heterozygous gain-of-function variants in ABCC9 and KCNJ8, encoding subunits of heterooctameric ATP-sensitive potassium (K_ATP) channels. CS shows considerable clinical overlap with Zimmermann-Laband syndrome (ZLS), a rare condition with coarse facial features, hypertrichosis, gingival overgrowth, intellectual disability of variable degree, and hypoplasia or aplasia of terminal phalanges and/or nails. ZLS is caused by heterozygous gain-of-function variants in KCNH1 or KCNN3, and gain-of-function KCNK4 variants underlie the clinically similar FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) syndrome; KCNH1, KCNN3 and KCNK4 encode potassium channels. Within our research project on ZLS, we performed targeted Sanger sequencing of ABCC9 in 15 individuals tested negative for a mutation in the ZLS-associated genes and found two individuals harboring a heterozygous pathogenic ABCC9 missense variant. Through a collaborative effort, we identified a total of nine individuals carrying a monoallelic ABCC9 variant: five sporadic patients and four members of two unrelated families. Among the six detected ABCC9 missense variants, four [p.(Pro252Leu), p.(Thr259Lys), p.(Ala1064Pro), and p.(Arg1197His)] were novel. Systematic assessment of the clinical features in the nine cases with an ABCC9 variant highlights the significant clinical overlap between ZLS and CS that includes early developmental delay, hypertrichosis, gingival overgrowth, joint laxity, and hypoplasia of terminal phalanges and nails. Gain of K⁺ channel activity possibly accounts for significant clinical similarities of CS, ZLS and FHEIG syndrome and defines a new subgroup of potassium channelopathies.     

Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: Additional findings or a new syndrome (ARCC-NDI)?

We report on 4 children from 2 unrelated families who appear to have the lethal ARC syndrome (arthrogryposis, renal tubular dysfunction, and cholestasis) together with the additional findings of nephrogenic diabetes insipidus and cerebral anomalies, including deafness. With increased survival time in our patients, paucity of the intrahepatic bile ductules and cholestasis progressed to cirrhosis, growth was severely impaired, and severe mental retardation became apparent. No evidence was found for peroxisomal, chromosomal, or mitochondrial disorders. We propose to amend the ARC mnemonic to ARCC-NDI (A-Arthrogryposis, R-renal Fanconi, C-cerebral, C-cholestasis, NDI-nephrogenic diabetes insipidus) to name the major manifestations of this syndrome, several of which have not been appreciated. Am. J. Med. Genet. 72:335–338, 1997. © 1997 Wiley-Liss, Inc.     

An unusual case of left venous renal entrapment syndrome: a new type of nutcracker phenomenon?

Left venous renal entrapment syndrome was observed during multidetector 64-row computer tomography and color Doppler ultrasonography in a 58-year-old Caucasian female hospitalized due to choledocholithiasis. The patient demonstrated no typical symptoms of nutcracker syndrome. The left renal vein (LRV) was compressed as it passed between the superior mesenteric artery and the right renal artery. The LRV lumen measured 1.7 × 7.8 mm (width × height) at the point of narrowing and 7.5 × 17 mm before this. Secondary to the nutcracker phenomenon, the course of left ovarian vein was winding and was significantly wider than the contralateral vessel.     

Noonan-like syndrome with loose anagen hair: a new syndrome?

We present three children with short stature, the same facial phenotype, macrocephaly, enlarged cerebral spinal fluid spaces, short neck with redundant skin, severe GH deficiency, mild psychomotor delay with attention deficit/hyperactivity disorder (ADHD), mild dilatation of the pulmonary root in two of them, and a unique combination of ectodermal abnormalities. Their appearance, not completely typical of Noonan syndrome, the behavioral phenotype, GH deficiency, darkly pigmented and hairless skin, and the unusual aspect of the hair, defined as loose anagen hair syndrome did not fit any known condition. We postulate that these children may represent a distinct, previously unreported syndrome that we would name "Noonan-like syndrome with loose anagen hair".     

Congenital myopathy,recurrent secretory diarrhea,bullous eruption of skin,microcephaly, and deafness: a new genetic syndrome?

We describe three siblings with congenital myopathy, bullous eruption of the skin, secretory diarrhea, apparent zinc deficiency, failure to thrive, deafness, and microcephaly. The parents are not consanguineous and there are no other affected relatives. This new syndrome, which follows an apparent autosomal recessive pattern, appears to be distinct from known syndromes of secretory diarrhea, myopathy, deafness, microcephaly, and zinc deficiency.     

Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): Old truths and a new syndrome?

There has been considerable interest in the role of environmental factors and the induction of autoimmunity and the ways by which they facilitate loss of tolerance. Clearly both genetic and environmental factors are incriminated, as evidenced by the lack of concordance in identical twins and the relatively recent identification of the shared epitope in rheumatoid arthritis. In this issue a new syndrome called 'Asia'-autoimmune/auto-inflammatory syndrome induced by adjuvants has been proposed. It is an intriguing issue and one that is likely to be provocative and lead to further biologic and molecular investigations.     

Growth failure, intracranial calcifications, acquired pancytopenia, and unusual humoral immunodeficiency: a genetic syndrome?

We report on two children who may represent a novel syndrome consisting of a deficiency of immunoglobulin-bearing B lymphocytes and serum antibody, deficient intrauterine and/or postnatal growth, intracranial calcifications, and acquired pancytopenia. Poor growth, intracranial calcifications, developmental delay, and hematological abnormalities are common manifestations of congenital infection. However, humoral immunodeficiency is not characteristic in these infections, and no infection was found on extensive evaluation. Rare genetic syndromes may mimic intrauterine infections and may also include immunodeficiency. However the children reported here lack important characteristics or share distinctive manifestations not described in these disorders. Infants presenting with apparent congenital infections in whom a specific infectious cause cannot be identified should be followed carefully with immunological evaluations since this disorder may be progressive and considerable morbidity is attributable to hematological and immunological manifestations.     

Epidermal nevus associated with a type I neurofibromatosis and a nephroblastoma: a new epidermal nevus syndrome?

We report the case of a 6-year-old boy who showed a large epidermal nevus mixed with a plexiform neurofibroma, which was associated with "café au lait" macules and a nephroblastoma. This association could not be classified in one of the five well defined epidermal nevus syndrome. To our knowledge this is the first time that this type of epidermal nevus syndrome has been described, which raises the question of the relationship between neurofibromatosis 1, nephroblastoma and epidermal nevus.     

Spondylocostal dysostosis,anal and genitourinary malformations in a fetal case: A new case of Casamassima–Morton–Nance syndrome?

Casamassima-Morton-Nance syndrome belongs to the heterogeneous group of spondylocostal dysostoses (SCD) represented by a large heterogeneous group in which diverse diagnoses, associations and modes of inheritance are found. Common features include segmentation abnormalities of the vertebrae and ribs. Here, we report on a fetal case with spondylocostal dysostosis, anal and genitourinary malformations and discuss Casamassima-Morton-Nance syndrome.     

Two sibs with microcephaly,hygroma colli,renal dysplasia,and cutaneous syndactyly: a new lethal MCA syndrome?

We report two sibs of Turkish descent with multiple congenital anomalies including severe microcephaly, hygroma colli, cystic renal dysplasia, and bilateral cutaneous syndactyly of toes IV-V. In addition, the second sib presented with bilateral fusion of the eyelids, a bicornuate uterus, and clitoromegaly. The parents are first cousins, which suggests autosomal recessive inheritance. In reviewing previously published reports, several cases were found with cerebral, renal, and digital anomalies as the main features. Several of the additional symptoms present in the second sib were suggestive of Fraser syndrome, but the severe microcephaly in both sibs is unusual. The differential diagnosis is discussed, including the possibility of an entirely new entity in the broad spectrum of syndromes with cerebral, renal, and digital anomalies.     

Blepharophimosis, corneal vascularization, deafness, and acroosteolysis: a "new" syndrome?

We report on a patient with blepharophimosis who after unsuccessful surgery developed progressive corneal vascularization. The patient had conductive hearing loss, acroosteolysis of the phalanges, arthropathy, loss of subcutaneous fat of the hands, feet and face, and oligospermia. He had had spontaneous pneumothorax four times. We have found no similar case reports in the literature and suggest that this is a new syndrome, which must be differentiated from hereditary mucoepithelial dysplasia, mandibuloacral dysplasia, keratitis-ichthyosis-deafness syndrome, Hajdu-Cheney syndrome, Penttinen syndrome, and mucopolysaccharidoses.     

Pulmonary agenesis, microphthalmia, and diaphragmatic defect (PMD): new syndrome or association?

We present the prenatal diagnosis of a 22-week-gestation fetus with unilateral pulmonary agenesis, diaphragmatic hernia, microphthalmia, pulmonary vessel agenesis, and intrauterine growth retardation. The "association" of pulmonary agenesis, diaphragmatic defect, and microphthalmia was described previously in two patients but the resemblance was not noted by the authors. While each case differs slightly in some of the associated anomalies, it is evident that the mainstay of diagnosis is similar to the case presented here and that this represents a new syndrome or association.     

Novel syndrome of cataracts, retinitis pigmentosa, late onset deafness and sperm abnormalities: a new Usher syndrome subtype with X-linked inheritance?

Tissues of the auditory, ocular and reproductive systems have some similarities in their protein families and structures. Consequently, syndromes comprising these systems are described. Hearing loss alone is a component of more than 400 known syndromes and is a common nonsyndromic congenital disorder. Here we describe a syndrome in five brothers with the distinctive presentation of late-onset progressive hearing loss, cataracts, retinitis pigmentosa, sperm motility and shape problems in a family from the Kurdish population in Iran. The clinical findings of these patients are presented in detail and compared to the classical Usher syndromes.