Oculoauriculofrontonasal syndrome (OAFNS) in a nine‐month‐old male

We report a nine‐month‐old Caucasian male with features seen in oculoauriculovertebral spectrum (OAVS) and frontonasal dysplasia sequence (FND) born to normal, non‐consanguineous parents and review the literature. His malformations included a left pre‐auricular skin tag, severely hypoplastic right pinna without an external canal, severely everted and hypoplastic left upper eyelid, bilateral cleft lip and palate, bifid broad nasal tip, ocular hypertelorism, micrognathia, hypoplastic mandible, an extra cervical rib on the left, hemivertebrae at T3–4, agenesis of the posterior corpus callosum with a midline lipoma, and an extra renal pelvis. This constellation of anomalies is consistent with the diagnosis of oculoauriculofrontonasal syndrome (OAFNS) which appears to be a distinct condition from either OAVS or FND but with overlapping features. © 2001 Wiley‐Liss, Inc.     

Deposition of cellular cementum onto hypoplastic enamel of fluorotic teeth in wild boars (<Emphasis Type="Italic">Sus scrofa</Emphasis> L.)

The nature of deposits present in hypoplastic defects of fluorotic enamel of wild boar teeth was studied by light microscopy and scanning electron microscopy. The fluorotic enamel showed different developmental abnormalities, denoting a severe disturbance of ameloblast function during the secretory stage of amelogenesis. These abnormalities included the occurrence of grossly accentuated incremental lines with associated zones of aprismatic enamel and the presence of different forms of hypoplastic defects. Two types of deposits were present on the hypoplastic enamel: cellular cementum and posteruptively acquired, presumably partially mineralized dental plaque. Coronal cementum is not normally formed in pig teeth. Presence of this tissue in fluorotic teeth of wild boars is seen as indicative of a premature disintegration of the enamel epithelium prior to the completion of amelogenesis. This was supposed to have resulted in a contact of mesenchymal cells of the dental follicle with the surface of the immature enamel and, in consequence, in a differentiation of these cells into cementoblasts. To our knowledge, this is the first study reporting the formation of coronal cementum as part of the spectrum of pathological changes in fluorotic teeth in a species whose tooth crowns are normally free of cementum.     

Tibial/femoral hypoplasia with “hook” pelvis: A potentially unique dysostosis

We report a 2‐year‐5‐month‐old girl with malformed lower limbs. The radiographic skeletal survey revealed agenesis of the ilio‐pubic rami with pubic dehiscence, right hip dislocation, bilateral coxa vara, short femurs, femoro‐tibial synchondrosis, bilateral hypoplastic tibiae more severe on the left side, and hypoplastic left calcaneus and talus. To the best of our knowledge, this combination of multiple congenital skeletal abnormalities has not been reported before. © 2002 Wiley‐Liss, Inc.     

A new multiple malformation syndrome of Müllerian dysgenesis and conductive hearing loss with facial hypoplasia, bilateral forearm deformity, brachydactyly, spinal stenosis and scoliosis

Multiple congenital malformations in a young girl with bilateral conductive hearing loss are described. Facial dysmorphic features include prominent supraorbital ridges, facial hypoplasia, facial asymmetry, downward-slanting palpebral fissures, high prominent nasal bridge with bifid nasal tip and a small lower jaw, and hypoplastic ear lobules with bilaterally narrow and oblique external auditory canals. Recognisable skeletal abnormalities include hypoplastic facial bones, hypoplastic clavicles, narrow and anteriorly sloping shoulders, bowing of both forearm bones, brachydactyly due to short metacarpals and hypoplastic terminal phalanges, thoracolumbar kyphoscoliosis, narrow transverse measurements of most vertebrae with prominent coccyx, spinal canal narrowing, hypoplasia of lower ilia, medially bowed femora, tibiae and fibulae and brachysyndactyly of the second, third and fourth toes bilaterally. Gynaecological evaluation revealed abnormalities of the Müllerian duct structures: urogenital sinus, a vestigial uterus, a posteriorly placed small but patent vagina and a septum at the vaginal introitus. The pattern of MCA probably refers to a new syndrome within the "community of syndromes" involving anomalies of the Müllerian duct structures, limbs, spine and external ears.     

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.     

左心发育不良综合征的产前超声诊断价值

目的探讨产前超声诊断胎儿左心发育不良综合征（HLHS）的诊断方法和价值。方法回顾性分析产前超声诊断为胎儿左心发育不良综合征的病例资料,对其超声特点进行分析,探讨其诊断要点。结果16例中经引产后尸检证实14例,2例失访。16例中四腔心切面均显示左、右心比例失常,左心狭小;三血管切面主、肺动脉内径比例失常,血流方向反向;主动脉弓切面显示主动脉弓内反向血流。结论产前超声对检出胎儿左心发育不良综合征具有极重要的价值。三血管切面主、肺动脉内径比例失常,血流方向反向;主动脉弓切面检出主动脉弓内反向血流对诊断HLHS具有重要的提示作用,四腔心切面是筛查HLHS的重要切面,多普勒超声是重要的和不可或缺的。     

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. Am. J. Med. Genet. 87:36–39, 1999. © 1999 Wiley-Liss, Inc.     

Maternal transmission of a mild Coffin–Siris syndrome phenotype caused by a SOX11 missense variant

Here we report for the first time on the maternal transmission of mild Coffin–Siris syndrome (CSS) caused by a SOX11 missense variant. We present two sisters with intellectual disability and muscular hypotonia born to non-consanguineous parents. Cogan ocular motor apraxia was present in both sisters. Body measurements were in a normal range. The mother and both daughters showed hypoplastic nails of the fifth toes. A missense variant in SOX11 [c.139 G > A; p.(Gly47Ser)] in both sisters and their mother was identified. Since 2014, variants in SOX11 are known to cause mild CSS. Most described patients showed intellectual disability, especially concerning acquired language. All of them had hypoplastic nails of the fifth toes. It is of note, that some of these patients show Cogan ocular motor apraxia. The facial dysmorphic features seem not to be specific. We suggest that the combination of Cogan ocular motor apraxia, hypoplastic nails of fifth toes, and developmental delay give the important diagnostic clue for a variant in the SOX11 gene (OMIM 615866, MR 27).Subject terms: ADHD, Autism spectrum disorders     

Hypoplastic myelodysplastic syndrome-a clinical,morphologic, or genetic diagnosis?

We report a middle-aged female with an 11-year history of nonprogressive pancytopenia and severely hypoplastic marrow with minimal morphologic dysplasia. A diagnosis of hypoplastic myelodysplastic syndrome (MDS) was made because of the finding of a persistent clonal abnormality, del(13)(q12q14), and the subsequent demonstration of a single Auer rod-containing blast in the peripheral blood smear. The case illustrates the problems in the differentiation between aplastic anemia and hypoplastic MDS.     

Testicular testosterone biosynthesis in male Saanen goats with XX sex chromosomes

Testosterone biosynthesis was examined in three pairs of twin male Saanen goats. In each pair, one goat was a phenotypically normal male of XY chromosome constitution; the other showed testicular hypoplasia of the sort typically associated with homozygosity for the dominant gene for polledness in genetic females, and was of XX chromosome constitution.
The histological and hormonal situations in the hypoplastic male goats resembled those found in Kleinfelter and XX human males, both in their nature and in their variability. Histological examination of the testes of the hypoplastic XX males showed various degrees of degeneration. In one case a "sperm pocket" full of spermatozoa was observed, and in this case sperm cells with heads separated from tails were observed in the semen. In the other two cases semen was devoid of sperm cells. In two cases plasma testosterone levels of the hypoplastic goats were lower than those of their normal counterparts, in one of the cases much lower. When testicular microsomal fractions of these goats were tested for their in vitro ability to bring about the conversion of androstenedione to testosterone, it was observed that 17β-hydroxysteroid dehydrogenase activity was either absent or lower in the hypoplastic goats than in their normal twins. In the third pair of animals, plasma testosterone levels were similar in both normal and hypoplastic animals. In this case, however, the increase in testosterone levels following HCG administration was lower in the hypoplastic than in the normal goats. 3β-hydroxysteroid dehydrogenase was the same in normal and hypoplastic goats. The variable effects on testosterone biosynthesis support the notion that the sex chromosomes, while affecting steroid biosynthesis in the testis, do so indirectly.     

Hypoplastic left heart in a female infant with partial trisomy 4q due to de novo 4;21 translocation

We present a female infant with mild dysmorphic features and congenital heart defect: hypoplastic left heart with aortic atresia and hypoplastic aortic arch, ventricular septal defect, and a nonrestrictive atrial communication. Chromosome analysis showed an unbalanced translocation that contained additional material from 4q translocated onto 21q. This resulted in partial trisomy 4 and monosomy for the 21q telomeric region. The derivative chromosome was characterized using G-banding, M-FISH, and whole chromosome painting. The karyotype was described as 46,XX,der(21)t(4;21)(q25;q22.3).ish(wcp4+;wcp21+). Additional analyses with FISH probes specific for 21q 22.3, 21q22.2, 21q21.1, and 21q11.2 did not indicate any chromosome 21 duplication within the derivative chromosome 21. Monosomy for the telomeric portion of 21q was demonstrated using a tel 21q probe (Oncor). The patient underwent stage 1 Norwood procedure to manage her heart defect. Poor feeding and failure to thrive complicated the postsurgical period. The child subsequently underwent funduplication and feeding tube placement, and at 4.5 months of age presented with microcephaly and developmental delay. Hypoplastic left heart was previously reported with increased frequency in relatively common numeric chromosomal aberrations, such as monosomy X, trisomies 21, 18, and 13, and in various structural chromosomal defects. Our report presents new evidence for the co-occurrence of hypoplastic left heart with a duplicated portion of chromosome 4 distal to 4q25. In addition, monosomy for the telomeric region of chromosome 21 may have implications in the phenotype.     

Pitt–Rogers–Danks syndrome: Further delineation

The Pitt–Rogers–Danks syndrome is an entity characterized by proportionate short stature and low weight of prenatal onset, moderate to severe mental retardation, seizures, and typical facial changes including microcephaly, telecanthus, upward or downward slanting palpebral fissures, prominent eyes, ocular abnormalities, hypoplastic maxilla, short philtrum, and large mouth. This is the seventh reported case, and the first one in which the patient also presents with optic atrophy. Autosomal recessive inheritance has been proposed until now, however, the increased paternal age seen in this case is suggestive of a possible autosomal dominant de novo mutation. © 1995 Wiley-Liss, Inc.     

A “new” lethal multiple congenital anomaly syndrome: Joint contractures,cerebellar hypoplasia,renal hypoplasia,urogenital anomalies,tongue cysts,shortness of limbs,eye abnormalities,defects of the heart,gallbladder agenesis,and ear malformations

Three cases of a lethal malformation syndrome with severe visceral anomalies were seen in two families and include one pair of sibs. The predominating external manifestations are mesomelic dwarfism, micrognathia, V-shaped upper lip, microglossia, thick alveolar ridges, ambiguous genitalia, webbed neck, highly arched palate, clubfeet, fused fontanelles, inclusion cysts of the tongue, four-finger creases, digital anomalies, apparently low-set ears, widely spaced nipples, and dislocated thighs and forearms. The internal findings include oligopapillary renal hypoplasia, severe congenital heart defect, cerebellar hypoplasia, pulmonary hypoplasia, hypoplastic larynx, and hypoplastic gallbladder. Other findings from the two autopsies and one clinical investigation not documented in all three patients include unilobar lungs, hydrocephalus, cataracts, microphthalmia, polydactyly, islet cell hyperplasia, suprapubic skin crease, urethral anomalies, and a decreased number of turns of the cochlea. The hypoplasia seen in the several affected organs is similar to the disordered development seen in experimental models of branching epithelial morphogenesis in which mesenchymal-epithelial interaction has been disrupted.     

dup(12p) and hypoplastic left heart

A six-week-old female infant with multiple congenital anomalies including a hypoplastic left-heart malformation was found to have duplication of 12p. Only two of 17 previously reported cases of dup (12p) had congenital heart disease, and both had hypoplastic left-heart abnormality.     

Long form of latent TGF‐β binding protein 1 (Ltbp1L) regulates cardiac valve development

Transforming Growth Factor β (TGF‐β) is crucial for valve development and homeostasis. The long form of Latent TGF‐β binding protein 1 (LTBP1L) covalently binds all TGF‐β isoforms and regulates their bioavailability. Ltbp1L expression analysis during valvulogenesis revealed two patterns of Ltbp1L production: an early one (E9.5–11.5) associated with endothelial‐to‐mesenchymal transformation (EMT); and a late one (E12.5 to birth) contemporaneous with valve remodeling. Similarly, histological analysis of Ltbp1L^?/? developing valves identified two different pathologies: generation of hypoplastic endocardial cushions in early valvulogenesis, followed by development of hyperplastic valves in late valvulogenesis. Ltbp1L promotes valve EMT, as Ltbp1L absence yields hypoplastic endocardial cushions in vivo and attenuated EMT in vitro. Ltbp1L^?/? valve hyperplasia in late valvuogenesis represents a consequence of prolonged EMT. We demonstrate that Ltbp1L is a major regulator of Tgf‐β activity during valvulogenesis since its absence results in a perturbed Tgf‐β pathway that causes all Ltbp1L^?/? valvular defects. Developmental Dynamics, 2011. © 2010 Wiley‐Liss, Inc.     

Enamel biorhythms of humans and great apes: the Havers‐Halberg Oscillation hypothesis reconsidered

The Havers‐Halberg Oscillation (HHO) hypothesis links evidence for the timing of a biorhythm retained in permanent tooth enamel (Retzius periodicity) to adult body mass and life history traits across mammals. Potentially, these links provide a way to access life history of fossil species from teeth. Recently we assessed intra‐specific predictions of the HHO on human children. We reported Retzius periodicity (RP) corresponded with enamel thickness, and cusp formation time, when calculated from isolated deciduous teeth. We proposed the biorhythm might not remain constant within an individual. Here, we test our findings. RP is compared between deciduous second and permanent first molars within the maxillae of four human children. Following this, we report the first RPs for deciduous teeth from modern great apes (n = 4), and compare these with new data for permanent teeth (n = 18) from these species, as well as with previously published values. We also explore RP in teeth that retain hypoplastic defects. Results show RP changed within the maxilla of each child, from thinner to thicker enameled molars, and from one side of a hypoplastic defect to the other. When considered alongside correlations between RP and cusp formation time, these observations provide further evidence that RP is associated with enamel growth processes and does not always remain constant within an individual. RP of 5 days for great ape deciduous teeth lay below the lowermost range of those from permanent teeth of modern orangutan and gorilla, and within the lowermost range of RPs from chimpanzee permanent teeth. Our data suggest associations between RP and enamel growth processes of humans might extend to great apes. These findings provide a new framework from which to develop the HHO hypothesis, which can incorporate enamel growth along with other physiological systems. Applications of the HHO to fossil teeth should avoid transferring RP between deciduous and permanent enamel, or including hypoplastic teeth.     

Guadalajara camptodactyly syndrome type II

Two sisters and an unrelated girl presented a distinct intrauterine growth retardation-malformation syndrome with short stature, microcephaly, pectus excavatum, hip dislocation, hypoplastic pubic region and genitalia, camptodactyly, talipes, shortened 2nd toes, hypoplastic patella and skeletal dysplasia probably due to homozygosity from an autosomal recessive gene.     

Autosomal dominant inheritance of left ventricular outflow tract obstruction

Most nonsyndromic congenital heart malformations (CHMs) in humans are multifactorial in origin, although an increasing number of monogenic cases have been reported recently. We describe here four new families with presumed autosomal dominant inheritance of left ventricular outflow tract obstruction (LVOTO), consisting of hypoplastic left heart (HLHS) or left ventricle (HLV), aortic valve stenosis (AS) and bicuspid aortic valve (BAV), hypoplastic aortic arch (HAA), and coarctation of the aorta (CoA). LVOTO in these families shows a wide clinical spectrum with some family members having severe anomalies such as hypoplastic left heart, and others only minor anomalies such as mild aortic valve stenosis. This supports the suggestion that all anomalies of the LVOTO spectrum are developmentally related and can be caused by a single gene defect.     

Prenatal exposure to valproic acid during pregnancy and limb deficiencies: A case‐control study

We conducted a case‐control study using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC) on the relationship between prenatal exposure to valproic acid (VPA) and the presence of limb deficiencies in newborn infants. Among a total of 22,294 consecutive malformed infants (once we excluded genetic syndromes) and 21,937 control infants with specified data on antiepileptic drugs during gestation, 57 malformed infants and 10 control infants were exposed to VPA during the first trimester of pregnancy. Of the total of malformed infants exposed to VPA, 36.8% (21/57) presented with congenital limb defects of different types (including overlapping digits, talipes, clubfoot, clinodactyly, arachnodactyly, hip dislocation, pre‐ and postaxial polydactyly, etc.), three of them having limb deficiencies. The result of the case‐control analysis shows a risk for limb deficiencies of odds ratio = 6.17 [confidence interval (CI) 1.28–29.66, P = 0.023], after controlling for potential confounder factors. If we consider that in our population the prevalence at birth of this type of defect is 6.88 per 10,000 livebirths (95% CI 6.43–7.36) we can estimate that the risk for women treated with VPA of having a baby with limb deficiencies would be around 0.42%. The limb deficiencies in the three patients exposed to VPA were the following: the first case was a newborn infant with hypoplasia of the left hand, the second patient was a newborn infant with unilateral forearm defect and hypoplastic first metacarpal bone in the left hand, and the third patient presented with short hands with hypoplastic first metacarpal bone, absent and hypoplastic phalanges, retrognathia, facial asymmetry, hypospadias, teleangiectatic angioma in skull, and hypotonia. Am. J. Med. Genet. 90:376–381, 2000. © 2000 Wiley‐Liss, Inc.     

Oral‐facial‐digital syndrome type 1 in males: Congenital heart defects are included in its phenotypic spectrum

Oral‐facial‐digital syndrome type 1 (OFD1; OMIM# 311200) is an X‐linked dominant ciliopathy caused by mutations in the OFD1 gene. This condition is characterized by facial anomalies and abnormalities of oral tissues, digits, brain, and kidneys. Almost all affected patients are female, as OFD1 is presumed to be lethal in males, mostly in the first or second trimester of pregnancy. Live born males with OFD1 are a rare occurrence, with only five reported patients to date. In four patients the presence of a congenital heart defect (CHD) was observed. Here, we report an affected male fetus with a hemizygous de novo mutation in OFD1 (c.2101C>T; p.(Gln701*)). Ultrasound examination demonstrated severe hydrocephalus, a hypoplastic cerebellum and a hypoplastic left ventricle of the heart. The pregnancy was terminated at 16 weeks of gestation because of poor prognosis. Post‐mortem examination of the fetus confirmed severe hypoplasia of the left ventricle of the heart. We emphasize that CHDs should be included in the phenotypic spectrum of OFD1 in males. This justifies molecular analysis of OFD1 when CHD is encountered prenatally in combination with one or more phenotypic features previously described in the OFD1 gene alteration spectrum. The underlying pathogenesis of CHD in OFD1 (and other ciliopathies) probably involves dysfunction of the primary cilia regarding coordination of left‐right signalling during early heart development. Whether these CHDs wholly or partly result from defective left right signalling, in which different types of cilia are known to play a critical role, remains a topic of research.