Refining the clinical phenotype associated with missense variants in exons 38 and 39 of KMT2D.

Loss-of-function variants in KMT2D are responsible for Kabuki syndrome type 1 (KS1). In the last 5 years, missense variants in exon 38 or 39 in KMT2D have been found in patients exhibiting a new phenotype with multiple malformations and absence of intellectual disability, distinct from KS1. To date, only 16 cases have been reported with classic features of hearing loss, abnormality of the ear, lacrimal duct defects, branchial sinus/neck pits, choanal atresia (CA), athelia, hypo(para)thyroidism, growth delay, and dental anomalies. We report here two families and one unpublished variant, refining the clinical and molecular knowledge on this new entity. Family 1 presented with apparently isolated autosomal dominant choanal atresia, in eight members across three generations. Exome sequencing (ES) in the proband and one cousin revealed a p.Glu3569Gly variant in exon 38 of KMT2D, segregating with choanal atresia in the family. Clinical reevaluation evidenced thyroid dysfunction, mild hearing anomalies, and hypoplastic nipple in some patients. Family 2 presented with nasolacrimal duct obstruction, hearing loss, mild facial features, unilateral axial polydactyly, and unilateral toe V-VI syndactyly. ES revealed a de novo already reported p.Arg3582Gln variant in exon 38 of KMT2D. Considering these results and the existing literature, we suspect that missense variants in exon 38 of KMT2D are responsible for phenotypes that are even milder (isolated CA) and broader (polydactyly) than what has been previously described.

[A rare cause of respiratory distress in the newborn]. / Une cause rare de détresse respiratoire du nouveau-né.

Respiratory distress in the newborn represents a real medical challenge from both the etiological and therapeutic points of view. The causes of respiratory distress are usually divided into two categories: upper and lower airway impairments, with the glottis as the reference level. Concerning the upper airway impairment in the newborn, nasal malformations are one of the main causes, choanal atresia in particular and more rarely congenital nasal pyriform aperture stenosis. The latter can be symptomatic in a variable degree, depending on the severity of the obstruction. Moreover, the potential syndromic character with the association of other malformations, such as single median incisor or intracranial midline anomalies, should systematically lead to the realisation of a cerebral MRI. Several lines of treatment are available depending on the clinical response ranging from conservative treatment to surgical intervention.

La détresse respiratoire du nouveau-né représente un véritable enjeu médical tant du point de vue étiologique que thérapeutique. On regroupe habituellement en deux catégories les causes de détresse respiratoire : les atteintes hautes et les atteintes basses avec, comme point de référence, le plan glottique. Concernant les atteintes hautes chez le nouveau-né, les malformations nasales sont une des principales causes, notamment l'atrésie des choanes et, plus rarement, la sténose congénitale des orifices piriformes. Cette dernière peut être symptomatique de manière variable en fonction de la gravité. De plus, le caractère syndromique potentiel avec l'association à d'autres malformations, comme l'incisive médiane unique ou des anomalies intracrâniennes de la ligne médiane, doivent systématiquement conduire à la réalisation d'une IRM cérébrale. Plusieurs lignes de traitement sont disponibles en fonction de la réponse clinique allant d'un traitement conservateur jusqu'à une intervention chirurgicale.

Pediatric unilateral isolated choanal atresia is not associated with mandibular condyle hypoplasia.

PURPOSE: We hypothesized that the ontogeny of unilateral isolated choanal atresia involves a field defect manifesting as ipsilateral mandibular condylar hypoplasia. The topic is important because the mechanism of the unilateral isolated choanal atresia is unknown. MATERIALS AND METHODS: Retrospective self-controlled case series. We included 20 patients (2 males and 18 females, ages 2 weeks to 13 years) with unilateral isolated non-syndromic choanal atresia. We studied their high-resolution computed tomographic scans. Two otolaryngologists measured the largest cross-sectional area of the mandibular condyle in the axial plane perpendicular to the posterior border of each mandibular ramus independently. Statistical significance and inter-rater agreement were calculated with paired Wilcoxon rank sum test and Spearman's non-parametric correlation coefficient respectively. RESULTS: Cross-sectional areas of the condyles ipsilateral to the choanal atresia were not statistically different than those of the contralateral condyle (P = 0.27). Inter-observer agreement of condyle areas was excellent: Spearman's r = 0.85 on the right and r = 0.94 on the left. CONCLUSIONS: In this cohort of children with the rarity of isolated non-syndromic unilateral congenital choanal atresia, no associated mandibular condyle hypoplasia was found. The data suggest that the underlying ontogeny was unlikely attributable to a field defect.

Clinical delineation of a subtype of frontonasal dysplasia with creased nasal ridge and upper limb anomalies: Report of six unrelated patients.

Frontonasal dysplasias are rare congenital malformations of frontonasal process-derived structures, characterized by median cleft, nasal anomalies, widely spaced eyes, and cranium bifidum occultum. Several entities of syndromic frontonasal dysplasia have been described, among which, to date, only a few have identified molecular bases. We clinically ascertained a cohort of 124 individuals referred for frontonasal dysplasia. We identified six individuals with a similar phenotype, including one discordant monozygous twin. Facial features were remarkable by nasal deformity with creased ridge and depressed or absent tip, widely spaced eyes, almond-shaped palpebral fissures, and downturned corners of the mouth. All had apparently normal psychomotor development. In addition, upper limb anomalies, frontonasal encephalocele, corpus callosum agenesis, choanal atresia, and congenital heart defect were observed. We identified five reports in the literature of patients presenting with the same phenotype. Exome sequencing was performed on DNA extracted from blood of two individuals, no candidate gene was identified. In conclusion, we report six novel simplex individuals presenting with a specific frontonasal dysplasia entity associating recognizable facial features, limb and visceral malformations, and apparently normal development. The identification of discordant monozygotic twins supports the hypothesis of a mosaic disorder. Although previous patients have been reported, this is the first series, allowing delineation of a clinical subtype of frontonasal dysplasia, paving the way toward the identification of its molecular etiology.

A review of craniofacial disorders caused by spliceosomal defects.

The spliceosome is a large ribonucleoprotein complex that removes introns from pre-mRNA transcripts. Mutations in EFTUD2, encoding a component of the major spliceosome, have recently been identified as the cause of mandibulofacial dysostosis, Guion-Almeida type (MFDGA), characterized by mandibulofacial dysostosis, microcephaly, external ear malformations and intellectual disability. Mutations in several other genes involved in spliceosomal function or linked aspects of mRNA processing have also recently been identified in human disorders with specific craniofacial malformations: SF3B4 in Nager syndrome, an acrofacial dysostosis (AFD); SNRPB in cerebrocostomandibular syndrome, characterized by Robin sequence and rib defects; EIF4A3 in the AFD Richieri-Costa-Pereira syndrome, characterized by Robin sequence, median mandibular cleft and limb defects; and TXNL4A in Burn-McKeown syndrome, involving specific craniofacial dysmorphisms. Here, we review phenotypic and molecular aspects of these syndromes. Given the apparent sensitivity of craniofacial development to defects in mRNA processing, it is possible that mutations in other proteins involved in spliceosomal function will emerge in the future as causative for related human disorders.

Successful Noninvasive Respiratory Management of an Infant with Bilateral Choanal Atresia and a Supernumerary Nostril Located on the Columella by a Mouthpiece: A Case Report.

BACKGROUND Choanal atresia with a supernumerary nostril located on the columella is extremely rare. Infants are obligate nasal breathers because the oral airway is invariably blocked during calm respiration. Infants breathe through the mouth only during crying, and they only have nasal breathing until 5 months of life. Congenital nasal anomalies have been reported to be fatal from birth, requiring tracheal intubation or tracheostomy in the early postnatal period. In these cases, it is crucial to maintain an adequate airway. CASE REPORT A 2948-g female infant was born at 40 weeks by normal vaginal delivery. Her Apgar scores were 9 and 9 at 1 and 5 min, respectively. She had retractive breathing, cyanosis, and a supernumerary nostril at birth. She had no other anomalies. Computed tomography showed bilateral membranous choanal atresia. She needed nasal continuous positive pressure or a high-flow nasal canula for oxygen desaturation during crying, apnea, and dyspnea. However, her respiratory symptoms did not improve completely. On day 25 of life, she was given a mouthpiece to support mouth breathing. Her respiratory symptoms improved gradually, and she was discharged on day 73 of life with a mouthpiece. CONCLUSIONS A very rare case of choanal atresia with a supernumerary nostril located on the columella was described. A mouthpiece was effective for breathing, obviating the need for emergency surgical intervention in the early postnatal period. Emergency procedures were avoided, probably because this case involved incomplete bilateral membranous choanal atresia rather than complete bony atresia.

Balloon dilation and transient stenting of unilateral membranous choanal atresia in a British Shorthair cat with chronic purulent rhinitis and ascending meningoencephalitis.

INTRODUCTION: Choanal atresia is a rare congenital anomaly in humans and animals, characterized by the absence of communication of one or both nasal cavities with the nasopharynx. The severity of clinical signs depends on the presence of unilateral versus bilateral stenosis as well as comorbidities. With bilateral atresia, respiration may be severely compromised particularly during sleep, as airflow can only occur when breathing through the open mouth. Various therapeutic modalities have been described in people and adopted for animals. All treatments may be associated with complications, the most important being post-therapeutic scar formation with re-stenosis. This report describes a 10-month-old British Shorthair cat with chronic unilateral serosal nasal discharge that changed to mucopurulent discharge. When acute neurological signs developed, the cat was presented to the veterinary hospital. A diagnosis of primary, membranous right sided choanal atresia was achieved via computed tomography (CT) and nasopharyngeal (posterior) rhinoscopy. Secondary changes included destructive rhinitis with progression to the CNS with a subdural empyema and meningoencephalitis. Retinal changes and aspiration bronchopneumonia were suspected additional complications. After recovery from the secondary infections, the membranous obstruction was perforated and dilated using a valvuloplasty balloon by an orthograde transnasal approach under endoscopic guidance from a retroflexed nasopharyngeal view. To prevent re-stenosis, a foley catheter was placed as a transient stent for 6 days. The cat recovered uneventfully and was asymptomatic after the stent removal. Endoscopic re-examination after 5 months confirmed a persistent opening and patency of the generated right choanal passage. The cat remains asymptomatic 10 months after the procedure. Transnasal endoscopic balloon dilation and transient stenting of choanal atresia is a minimally invasive and relatively simple procedure with potentially sustained success.

INTRODUCTION: L'atrésie des choanes est une anomalie congénitale rare chez l'homme et l'animal, caractérisée par l'absence de communication d'une ou des deux cavités nasales avec le nasopharynx. La gravité des signes cliniques dépend de la présence d'une sténose unilatérale ou bilatérale, ainsi que des comorbidités. En cas d'atrésie bilatérale, la respiration peut être gravement compromise, en particulier pendant le sommeil, car l'air ne peut circuler que par la bouche ouverte. Diverses modalités thérapeutiques ont été décrites chez l'homme et adaptées pour les animaux. Tous les traitements peuvent être associés à des complications, la plus importante étant la formation de cicatrices post-thérapeutiques avec resténose. Ce rapport décrit un chat British Shorthair de 10 mois présentant un écoulement nasal séreux unilatéral chronique qui s'est finalement transformé en un écoulement muco-purulent. Lorsque des signes neurologiques aigus sont apparus, le chat a été présenté à l'hôpital vétérinaire. La tomodensitométrie (CT) et la rhinoscopie nasopharyngée (postérieure) ont permis de diagnostiquer une atrésie choanale primaire membraneuse du côté droit. Les altératiins secondaires comprenaient une rhinite destructrice avec une progression vers le SNC avec empyème sous-dural et méningo-encéphalite. Des altérations de la rétine et une bronchopneumonie par aspiration étaient des complications supplémentaires présumées. Après guérison des infections secondaires, l'obstruction membraneuse a été perforée et dilatée à l'aide d'un ballonnet de valvuloplastie par une approche transnasale orthograde sous guidage endoscopique à partir d'une vue nasopharyngée rétrofléchie. Pour éviter une nouvelle sténose, une sonde de Foley a été placée comme stent transitoire pendant 6 jours. Le chat s'est rétabli sans incident et était asymptomatique après le retrait du stent. Le réexamen endoscopique effectué 5 mois plus tard a confirmé la persistance de l'ouverture et de la perméabilité de la voie choanale droite générée. Le chat reste asymptomatique 10 mois après l'intervention. La dilatation endoscopique transnasale par ballonnet et la pose d'une endoprothèse transitoire dans le cas d'une atrésie des choanes est une procédure peu invasive et relativement simple dont le succès peut être durable.

Nasal Obstruction in the Infant.

Neonatal nasal obstruction is common in both the hospital and clinic settings. Causes can range from rhinitis to congenital masses, with a wide variety of congenital nasal masses described. A complete history and physical examination are necessary for correct diagnosis and management. Arhinia and bilateral choanal atresia will present with complete obstruction leading to forced mouth breathing. Partial obstruction will require assessment of nasal patency with possible nasal endoscopy and imaging. Medical and surgical options for treatment are discussed.

A patient with mosaic USP9X gene variant.

The finding of USP9X variants in females has been associated with female-restricted X-linked mental retardation (MRXS99F), a rare syndrome featured by developmental delay and distinct congenital anomalies. Here, we report a female fetus with MRXS99F due to a novel frameshift variant, c.6679_6685delAAATTATinsTCCTG (p.Lys2227SerfsTer2) in USP9X, which was present in a mosaic state in the amniocytes and in the peripheral blood after birth (14% and 30%, respectively). The X methylation status analysis displayed a partially skewed X-inactivation with 80% of inactive paternal X. The first signs of the MRXS99F were prenatally detected at 20 weeks, with an enlarged posterior cranial fossa, an upward rotation of the cerebellar vermis and partial corpus callosum agenesis, together with a cardiac septal defect and a single umbilical artery. After birth and during postnatal follow-up the anal anteriorization and the presence of a bilateral membranous choanal atresia were noted, whereas the MRI revealed the hypo/aplasia of the olfactory bulbs, a widening of the subarachnoid spaces and a delay in the myelinisation. During the 18-months follow-up a severe growth and global developmental delay, together with a bilateral moderate deafness with a threshold at 40 dB, dental enamel erosions and an initial scoliosis were observed. We report the prenatal and postnatal features of a classical MRXS99F phenotype and a mosaic USP9X frameshift variant with a partially skewed X inactivation and discuss genotype/phenotype correlations in view of the published studies so far.

Tbx22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes.

Craniofacial defects involving the lip and/or palate are among the most common human birth defects. X-linked cleft palate and ankyloglossia results from loss-of-function mutations in the gene encoding the T-box transcription factor TBX22. Further studies show that TBX22 mutations are also found in around 5% of non-syndromic cleft palate patients. Although palate defects are obvious at birth, the underlying developmental pathogenesis remains unclear. Here, we report a Tbx22(null) mouse, which has a submucous cleft palate (SMCP) and ankyloglossia, similar to the human phenotype, with a small minority showing overt clefts. We also find persistent oro-nasal membranes or, in some mice a partial rupture, resulting in choanal atresia. Each of these defects can cause severe breathing and/or feeding difficulties in the newborn pups, which results in approximately 50% post-natal lethality. Analysis of the craniofacial skeleton demonstrates a marked reduction in bone formation in the posterior hard palate, resulting in the classic notch associated with SMCP. Our results suggest that Tbx22 plays an important role in the osteogenic patterning of the posterior hard palate. Ossification is severely reduced after condensation of the palatal mesenchyme, resulting from a delay in the maturation of osteoblasts. Rather than having a major role in palatal shelf closure, we show that Tbx22 is an important determinant for intramembranous bone formation in the posterior hard palate, which underpins normal palate development and function. These findings could have important implications for the molecular diagnosis in patients with isolated SMCP and/or unexplained choanal atresia.

Osteosclerotic bone dysplasia in siblings with a Fam20C mutation.

Raine syndrome is an autosomal recessive disorder caused by mutations in the FAM20C gene. FAM20C codes for the human homolog of DMP4, a dentin matrix protein highly expressed in odontoblasts and moderately in bone. DMP4 is probably playing a role in the mineralization process. Since the first case reported in 1989 by Raine et al. 21 cases have been published delineating a phenotype which associates dysmorphic features, cerebral calcifications, choanal atresia or stenosis and thoracic/pulmonary hypoplasia. Kan and Kozlowski suggested the name of Raine syndrome to describe this new lethal osteosclerotic bone dysplasia. All the cases described were lethal during the neonatal period except for the last two reported patients aged 8 and 11 years who presented severe mental retardation. Here we describe two sisters, with an attenuated phenotype of Raine syndrome, who present an unexpectedly normal psychomotor development at ages 4 and 1, respectively. Identification of a homozygous mutation in the FAM20C gene confirmed the Raine syndrome diagnosis, thus contributing to the expansion of the Raine syndrome phenotype. This case report also prompted us to revisit the FAM20 gene classification and allowed us to highlight the ancestral status of Fam20C.

Nasal cavity shape in unilateral choanal atresia and the role of fetal ventilation in facial growth.

OBJECTIVE: The respiratory movements of fetal amniotic fluid areconsidered by certains cleft surgery teams to contribute to the growth of the nasal cavities (NC). To assess this functional hypothesis, we considered a group of patients with unilateral choanal atresia (CA) as a model of unilateral absence of amniotic fluid flux in the NC, and compared their NCs shape to age-matched controls. MATERIAL AND METHODS: Three-dimensional reconstructions of NC were performed using Avizo 9.7 (Thermo Fisher Scientific, MA, USA), based on CT-scans of 32 patients with unilateral CA and 96 age- and gender-matched controls. Landmarks were placed on anatomical structures of NC. Procrustes superimpositions and principal component analysis were performed. Anatomically relevant Euclidean distances were computed using the coordinates of selected landmarks - maxillary length, piriform orifice width, choanal width - and tested using multivariate analysis. Growth rates between patients and controls for these distances were screened for correlations. RESULTS: The atretic NC was significantly deformed when compared to the control cases: Procrustes distance was 0.28 (P<0.0001). The maxillary length and width of the atretic choana were significantly decreased compared to controls (-2.95mm and -1.35mm respectively, P<0.001). There were no differences in growth rates between CA and controls, except for the choanal width on the atretic side. CONCLUSION: NCs in CA were significantly different from controls. More precisely, the maxillary length was significantly reduced in the CA group. There was no other major shape difference between the NC in CA and controls. NC seems to develop despite abnormal fetal ventilation.

Partial deletion of the long arm of chromosome 13 (q32q33.2) associated with mental retardation, choanal atresia and fish mouth.

13q deletion syndrome is characterized by mental and motor retardation, craniofacial dysmorphic facial appearance and various congenital malformations. In this article, we present a new case with 13q deletion syndrome phenotypically characterized by fish mouth, choanal atresia and severe mental and motor retardation. In order to determine the certain localization of deleted region high resolution multicolor-banding technique was performed and the karyotype determined as 46,XX,del(13)(q32q33.2). To come in future to a genotype-phenotype correlation, it is very important to delineate the deleted region in such cases in detail by cytogenetic/ molecular cytogenetic methods.

Single median maxillary central incisor syndrome and variant in SMO gene associated with SHH pathway.

Solitary median maxillary central incisor syndrome (SMMCI) is a rare congenital oronasal-dental midline anomaly. The aim of this paper is a presentation of a patient with SMMCI without other visible dentofacial anomalies, with a potentially new molecular etiology consisting of a gene-gene reaction and conservative therapeutic approach to nasal obstruction. Potentially pathogenic variants in the SMO gene (p.Gly422Glu) and in P2RY13 gene (p.Trp205*) inherited from the probant's father, and in the PLD2 gene (p.Gln319fs), inherited from the mother were found. A multidisciplinary approach is necessary for the management of patients with SMMCI, including a genetic consultation with genetic tests.

Cleft palate in Pfeiffer syndrome.

The frequency of associated cleft palate is known to be high in some fibroblast growth factor receptor 2 (FGFR2)-mediated craniosynostosis syndromes, such as Apert syndrome. However, there is little information on the frequency of palatal clefts in the FGFR2-mediated disorder, that is, Pfeiffer syndrome. The purpose of this study was to determine the frequency of palatal clefts in patients with Pfeiffer syndrome. The records of patients with Pfeiffer syndrome managed in our craniofacial unit were reviewed. Only patients with a confirmed diagnosis of Pfeiffer syndrome were included. Diagnostic criteria were as follows: characteristic mutations in FGFR1 or FGFR2 or, in the absence of genetic testing, clinical findings consistent with Pfeiffer syndrome as determined by a clinical geneticist or our most experienced surgeon (J.B.M.). Only 2 clefts were noted in 25 patients (8%), including 1 with a submucous cleft and 1 with an overt palatal cleft. Many patients (87%) were described as having a high-arched and narrow palate, and 1 had a low, broad palate. Nine patients were noted to have choanal atresia or stenosis. Clefting of the palate does occur in Pfeiffer syndrome but at a low frequency.

Curvilinear mandibular distraction in a patient with mandibulofacial dysostosis associated with Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia or hypoplasia presenting in infancy as a macrocytic anemia. It has been linked to a gene defect resulting in the absence of specific ribosomal proteins that enable erythroid maturation. Treacher Collins syndrome is also associated with defective ribosomal biogenesis. Fifty percent of patients with DBA also present with additional physical abnormalities including growth delay, craniofacial abnormalities, upper limp abnormalities, cardiac defects, urogenital malformations, and cleft palate. Upper airway obstruction may be a complication from craniofacial disorders and may be responsible for life-threatening sleep apnea that may result in pneumonia or respiratory failure. This report is of a patient with DBA who presented at birth with respiratory distress secondary to tongue-based obstruction of the airway due to mandibulofacial dysostosis leading to need for intubation. In an effort to avoid a tracheostomy, the patient underwent bilateral internal mandibular osteodistraction on day 4 of life with a latency period of 0 days and a distraction at a rate of 2 mm/d for 10 days until a class 3 dental occlusion existed with 5 mm of overcorrection. In addition, the patient was born with choanal atresia that was repaired at day 30 of life. After completion of the mandibular distraction, the patient has avoided tracheostomy and is now 6 months of age. Recent polysomnogram has demonstrated no significant apnea or hypopnea.

Use of a novel surgical approach for treatment of complete bilateral membranous choanal atresia in an alpaca cria.

CASE DESCRIPTION A 4-hour-old 6.3-kg (13.9-lb) female alpaca cria was evaluated because of severe respiratory distress and difficulty nursing since birth. CLINICAL FINDINGS The cria had open-mouth breathing and cyanotic membranes, with no airflow evident from either nostril. Supplemental oxygen was delivered, and the patient was anesthetized and intubated orotracheally; a CT evaluation of the head confirmed bilateral membranous obstruction of the nasal cavities, consistent with complete bilateral choanal atresia. TREATMENT AND OUTCOME Choanal atresia was treated with an endoscopically assisted balloon-dilation technique, and temporary tracheostomy was performed. Stenosis recurred, requiring revision of the repair and intranasal stent placement 3 days after the first surgery. The tracheostomy tube was removed the next day. Complications during hospitalization included mucoid obstruction of the tracheostomy tube, granulation tissue development in the trachea near the tracheostomy site, mucoid stent obstruction, aspiration pneumonia, and presumed partial failure of passive transfer of immunity. The stents were removed 2 weeks after admission, and the cria was discharged 3 days later. The owner was advised that the animal should not be bred. At last follow-up 3 years later, the alpaca was doing well. CLINICAL RELEVANCE Surgical treatment with a balloon-dilation technique and placement of nasal stents with endoscopic guidance were curative in this neonatal alpaca with bilateral membranous choanal atresia. Computed tomography was useful to determine the nature of the atresia and aid surgical planning. Because a genetic component is likely, owners should be advised to prevent affected animals from breeding.

Characteristics of lacrimo-auriculo-dento-digital (LADD) syndrome: case report of a family and literature review.

We describe a family with lacrimo-auriculo-dento-digital syndrome (LADD). A 13-year-old boy had cup-shaped ears, deafness, unilateral choanal atresia, bilateral nasolacrimal duct obstruction, xerostomia, alacrima due to congenital absence of lacrimal glands, agenesis of salivary glands, chronic dacryocystitis, keratoconjunctivitis sicca, ptosis, nail dysplasia of the thumb, shortness of fifth toe, temporal bone abnormality and epilepsy. His younger sister had shortened middle phalanx of fifth digits. His middle sister had hypodontia, shortened distal phalanx of fifth digit, agenesis of salivary glands, mild hearing loss and exotropia. His older sister had left nasolacrimal duct obstruction and aplasia of both parotid glands. The oldest sister had hypodontia and divergent excess exotropia. His mother had hypodontia. These findings are consistent with LADD syndrome. An autosomal dominant pattern of inheritance with variable expressivity has been demonstrated. Renal and uro-genital anomalies have been noted variably.