Management of Tracheobronchial Stenosis in Chondrodysplasia Punctata.

Chondrodysplasia punctata (CDP) is a rare congenital syndrome characterized by aberrant, punctate deposition of calcium during endochondral bone formation, resulting in the characteristic finding of epiphyseal stippling on radiographs. While otolaryngologic manifestations such as nasomaxillary hypoplasia and mixed hearing loss are common, tracheobronchial calcification occurs rarely in neonates with CDP. The management of CDP-related airway stenosis is complex and there is limited literature pertaining to outcomes of airway interventions. Herein, we describe the clinical course and outcome of tracheal dilation for a newborn patient with CDP. Laryngoscope, 134:1464-1468, 2024.

A new case of Greenberg dysplasia and literature review suggest that Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia are allelic disorders.

BACKGROUND: Greenberg dysplasia is a rare, autosomal recessive, prenatal lethal bone dysplasia caused by biallelic pathogenic variants in the lamin B receptor (LBR) gene. Pathogenic variants in LBR are also associated with Pelger-Huët anomaly, an autosomal dominant benign abnormality of the nuclear shape and chromatin organization of blood granulocytes, and Pelger-Huët anomaly with variable skeletal anomalies, a mild, regressing to moderate-severe autosomal recessive condition. Conditions with abnormal sterol metabolism and different genetic basis have clinical and radiographic features similar to Greenberg dysplasia, for example X-linked dominant chondrodysplasia punctata, Conradi-Hünermann type, and CHILD syndrome, and other conditions with unknown genetic etiology display very similar features, for example, dappled diaphyseal dysplasia and Astley-Kendall dysplasia. METHODS: We present a fetus with typical clinical and radiographic features of Greenberg dysplasia, and review the literature. RESULTS: Genetic testing confirmed the diagnosis Greenberg dysplasia: homozygosity for a pathogenic variant in LBR. CONCLUSION: Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley-Kendall dysplasia, we suggest that these are allelic disorders.

Prenatal findings in a fetus with X-linked recessive type of chondrodysplasia punctata (CDPX1): a case report with novel mutation.

BACKGROUND: X-linked recessive chondrodysplasia punctate (CDPX1) is a rare congenital disorder of bone and cartilage development, caused by a mutation in the arylsulfatase E (ARSE) gene located on chromosome Xp22.3. Although most of the affected men had mild symptoms, some had more severe symptoms, and had a poor prognosis. CASE PRESENTATION: We present the case of a male fetus diagnosed with CDPX1. Ultrasound clearly showed that hypoplasia of the midface, flatness of face, low flatness of the nose, collapse of the tip of the nose, accompanied by severe spinal stenosis and secondary ossification center of the femoral metaphysis appeared in advance. Chromosome analysis of the amniotic fluid cells revealed 46, XY. Whole exome sequencing showed that there was a novel missense mutation of c.640G > A in ARSE gene on X chromosome. Three protein function prediction software FATHMM、Polyphen-2、PROVEAN have shown that the novel missense mutation of c.640G > A in this study was pathogenic. CONCLUSIONS: Our case is a novel mutation and presents a typical characterization of the disease, which can expand the spectrum of mutations of the ARSE gene and is helpful for prenatal ultrasound diagnosis of this disease.

Severe nasomaxillary hypoplasia (Binder phenotype) on prenatal US/MRI: an important marker for the prenatal diagnosis of chondrodysplasia punctata.

BACKGROUND: Chondrodysplasia punctata is a skeletal dysplasia caused by a diverse spectrum of etiologies, with outcomes ranging from antenatal demise to a normal life span. Prenatal detection can be challenging. OBJECTIVE: To review a series of cases of chondrodysplasia punctata associated with nasomaxillary hypoplasia, known as the Binder phenotype, and to highlight prenatal ultrasound and MRI findings, as well as postnatal MRI and radiographic findings. MATERIALS AND METHODS: We retrospectively reviewed ultrasound, MRI and radiographic imaging findings in postnatally confirmed cases of chondrodysplasia punctata from 2001 to 2017. We analyzed prenatal findings and correlated them with maternal history, postnatal imaging, phenotype, genetics and outcome. RESULTS: We identified eight cases, all with prenatal US and six of eight with prenatal MRI between 18 weeks and 32 weeks of gestational age. Reasons for referral included midface hypoplasia in four cases; family history in one case; intrauterine growth restriction in one case; short long-bones, intrauterine growth restriction and multicystic kidney in one case; and multiple anomalies in one case. In six cases, postnatal radiographs were performed. In four cases, postnatal spine MRI imaging was performed. The diagnosis of chondrodysplasia punctata was suggested in prenatal reports in six of eight fetuses. Seven of eight fetuses had Binder phenotype with severe nasomaxillary hypoplasia. Limb length was mildly symmetrically short in four of eight cases and normal in four of eight fetuses. Two of eight fetuses had epiphyseal stippling identified prenatally by US; this was present postnatally in six neonates on radiographs. Hand and foot abnormalities of brachytelephalangy were not detected on the prenatal US or MRI but were present in six of eigth fetuses on postnatal radiographs or physical exam. Four of eight fetuses had prenatal spine irregularity on US from subtle stippling. Six of eight had spine stippling on postnatal radiographs. One fetus had cervicothoracic kyphosis on prenatal US and MRI, and this was postnatally present in one additional neonate. One case had prenatally suspected C1 spinal stenosis with possible cord compression, and this was confirmed postnatally by MRI. There was a maternal history of systemic lupus erythematosus in two and hyperemesis gravidarum in one. Outcomes included one termination and seven survivors. CONCLUSION: Chondrodysplasia punctata can be identified prenatally but findings are often subtle. The diagnosis should be considered when a fetus presents with a hypoplastic midface known as the Binder phenotype. Maternal history of lupus, or other autoimmune diseases or hyperemesis gravidarum can help support the diagnosis.

Surgical management of cervical spine deformity in chondrodysplasia punctata.

OBJECTIVE Chondrodysplasia punctata (CDP), a rare skeletal dysplasia, can lead to cervical spine instability and deformity. However, an optimal neurosurgical intervention has yet to be established. Thus, a retrospective study was conducted to assess the efficacy of various surgical interventions for children with CDP. METHODS The authors retrospectively reviewed 9 cases of CDP in which cervical decompression with or without posterior fusion was performed between April 2007 and May 2016. Patient demographics, preoperative clinical conditions, radiographic findings, surgical procedures, and the postoperative course were analyzed in detail. RESULTS A total of 12 operations were carried out in 9 patients (8 male, 1 female) during the study period. The patients' ages at the initial surgery ranged from 2 months to 2 years. Seven of the children had CDPX1, 1 had CDPX2, and 1 had tibia-metacarpal type CDP (CDP-TM). The lesion occurred at the craniovertebral junction (CVJ) in 7 cases and involved a subaxial deformity in 2 cases. The initial surgery was C-1 laminectomy with occipitocervical fusion (OCF) followed by halo external fixation in 5 cases, OCF alone in 1 case, and C-1 laminectomy alone in 3 cases. Three children required additional surgery. In one of these cases, a staged operation was required because the patient's head was too small to attach a halo ring at the time of the initial procedure (C-1 laminectomy). In another case, OCF was performed 11 months after C-1 laminectomy because of intramedullary signal change on serial MRI, although the child remained asymptomatic. In the third case, additional posterior fusion was performed 17 months after an initial laminectomy and OCF due to newly developed cervical dislocation caudal to the original fusion. This last patient required a third operation 9 months after the second because of deep wound infection. Surgery improved the motor function of all 7 children with CDPX1, but 3 children who had already suffered respiratory failure preoperatively required continued respiratory support. At the time of this report, 7 of the 9 children were alive and in stable condition. One child died due to restrictive respiratory insufficiency, and another died in an accident unrelated to CDP. CONCLUSIONS Surgical decompression with or without fusion for CVJ and subaxial cervical lesions in infants and toddlers with CDP generally saves lives and increases the likelihood of motor function recovery. However, in this case series the patients' preoperative condition had a strong effect on postoperative respiratory function. The surgery was not straightforward, and a second operation was required in some cases. Nevertheless, the findings indicate that early surgical intervention for CDP with cervical involvement is feasible, suggesting that the role of neurosurgery should be reevaluated.

Radiological picture of premature baby with manifestation of brachytelephalangic type chondrodysplasia punctata, myelomalacia.

Chondrodysplasia punctata (CDP) is a heterogeneous disease with multiple syndromic types and characterization of the CDP subtype is important for prognostic purposes. The aim of this study is to provide information about brachytelephalangic CDP, discuss its radiographic findings and emphasize the importance of cervical spine findings. Physicians must be aware of the potentially serious complications of CDP especially its cervical spine findings. In order to prevent morbidity and mortality, early imaging with CT and MRI is recommended.

Unfused Liver Segments: a Case Report of an Unknown Phenotype of the Conradi-Hünermann-Happle Syndrome.

BACKGROUND: Since its description in 1957, Couinaud`s classification of the segmental organization of the liver has remained valid. However, recent investigations by 3-dimensional computed tomography suggest a significant variability of the vascular anatomy and segment volume. Here, we report a surprise finding during the laparoscopic cholecystectomy of a patient with Conradi-Hünermann-Happle syndrome, in whom the liver segments were not fused. CASE REPORT: Laparoscopic cholecystectomy was performed because of recurrent biliary pancreatitis in a 47 year-old male patient, who had been diagnosed with Conradi-Hünermann-Happle syndrome. Upon direct view, the liver parenchyma appeared normal, but liver segments were separated and connected by fibrous bridges containing vascular structures, only. Since the hilar anatomy was unclear, an open cholecystectomy was performed without technical difficulties and the postoperative course was uneventful. Postoperatively, magnetic resonance imaging was performed, which revealed a trifurcation of the portal vein and a right bile duct draining into the left main duct. Intersegmental signal alterations corresponded to the fibrous bands seen during laparoscopy. CONCLUSIONS: The intraoperative findings of this case confirm the segmental organization of hepatic anatomy proposed by Couinaud. The first description of such an unusual anatomical variant in an extremely rare genetic disorder strongly suggests an association with the genetic background of the syndrome. The established abnormalities of cholesterol biosynthesis in patients with Conradi-Hünermann-Happle syndrome may well explain the observed liver anomaly, which is a novel phenotype of this syndrome. Based on this case, we suggest a potential involvement of the mutation in the emopamil-binding protein gene in liver development and regeneration.

Effect of Intrathecal Baclofen on Delayed-Onset Paroxysmal Dystonia due to Compression Injury Resulting From Congenital and Progressive Spinal Bone Deformities in Chondrodysplasia Punctata.

BACKGROUND: Dystonia due to spinal lesions in adult patients is characterized by the provocation and/or amelioration of the spasm by somatosensory stimulation with a sensory trick. PATIENT DESCRIPTION: An infant with brachytelephalangic chondrodysplasia punctata developed flaccid tetraplegia due to cervical cord compression resulting from congenital atlantoaxial dislocation. Episodic, tonic extension of the extremities, neck, and trunk had appeared daily since age two years and was often provoked by tactile stimulation. Although decompression surgery was performed at age three years, progressive spinal deformity resulted in the aggravation of episodic dystonia thereafter, lasting for hours. Foot dorsiflexion and wearing a truncal brace for scoliosis inhibited these spasms. Intrathecal baclofen bolus injection transiently ameliorated the paroxysmal dystonia and detrusor-sphincter dyssynergia in the lower urinary tract. CONCLUSION: Paroxysmal dystonia is unusual in children with spinal cord lesions; however, it should be recognized for appropriate individualized clinical management.

Severe X-linked chondrodysplasia punctata in nine new female fetuses.

OBJECTIVES: Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. METHODS: To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. RESULTS: The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. CONCLUSION: Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations.

Natural history and management of cervical spine disease in chondrodysplasia punctata and coumarin embryopathy.

PURPOSE: Chondrodysplasia punctata (CDP) is a group of skeletal dysplasias manifesting with progressive cervical instability that leads to neurological deficits and eventual death. The major clinical features of CDP also present in a phenocopy known as coumarin embryopathy (CE) which results from coumarin exposure during pregnancy. The objective of this study was to assess treatment strategies employed for children affected by CDP or CE with cervical instability and to determine a strategy on how best to diagnose and treat affected neonates. METHODS: We performed a systematic review of the English literature for cases reporting cervical spine involvement in CDP and CE and identified 44 such patients. We extracted clinical information on these disorders and identified two patients from our craniovertebral junction database of over 6,000 patients evaluated at our institution. RESULTS: Patients most frequently present with hyperreflexia (21%) and weakness (21%), and there were various conservative treatment strategies. Twenty-one percent of patients who were treated conservatively had neurological complications in their clinical course. There were two deaths reported, one resulting from conservative treatment and one from surgical treatment. We also report long-term follow-up analysis for a patient treated at our institution for the last 30 years and agree with all other reports that suggest that monitoring patients for neurological changes is essential to prevent further neurological injury. CONCLUSIONS: This study emphasizes the need for careful neurological and surgical evaluation of pediatric patients with cervical spine abnormalities affected by CDP or CE in order to prevent progressive instability.

Brachytelephalangic chondrodysplasia punctata: prenatal diagnosis and postnatal outcome.

We report the prenatal management of a brachytelephalangic chondrodysplasia punctata (CDPX1) case and how postnatal findings confirmed the diagnosis. The mother was initially referred after ultrasound revealed an abnormal fetal mid-face and punctuation of upper femoral epiphyses. Chondrodysplasia punctata (CP) with Binder anomaly was suspected. 3D-HCT revealed brachytelephalangy suggesting CDPX1. At birth, mid-face hypoplasia was marked. Postnatal imaging and genetic analysis confirmed the initial diagnosis. Binder anomaly is probably always associated with CP. The newly revised CP classification facilitates the diagnosis. The main etiologies are metabolic and chromosomal abnormalities, and arylsulfatase E enzyme dysfunction. Thus, screening for arylsulfatase E mutation is mandatory for an accurate diagnosis and can lead to better delineation among CP etiologies associated with a Binder phenotype.

Prenatal diagnosis of brachytelephalangic chondrodysplasia punctata: case report.

Brachytelephalangic chondrodysplasia punctata is a rare congenital skeletal dysplasia. Within the heterogeneous group of chondrodysplasia punctata, the brachytelephalangic type is noteworthy because it has a better prognosis than do the other types. We report a case of brachytelephalangic chondrodysplasia punctata diagnosed by ultrasound imaging at 30 weeks' gestation; it was associated with polyhydramnios and a normal cervical spinal canal. Imaging features are described and differential diagnosis with other forms of chondrodysplasia punctata is discussed.

Severe tracheobronchial stenosis and cervical vertebral subluxation in X-linked recessive chondrodysplasia punctata.

Radiologic manifestations of X-linked chondrodysplasia punctata (CDPX1) typically include chondrodysplasia, epiphyseal stippling, punctate calcification of cartilage, distal phalangeal hypoplasia, and nasal/midface hypoplasia. We present an infant with CDPX1 demonstrating calcification and stenosis of the entire trachea and mainstem bronchi, as well as possible anterior C1 subluxation due to progression of congenital vertebral dysplasia.

Binder phenotype: clinical and etiological heterogeneity of the so-called Binder maxillonasal dysplasia in prenatally diagnosed cases, and review of the literature.

OBJECTIVE: Prenatal Binder profile is a well known clinical phenotype, defined by a flat profile without nasal eminence, contrasting with nasal bones of normal length. Binder profile results of a hypoplasia of the nasal pyramid (sometimes referred to as maxillonasal dysplasia). We report 8 fetuses prenatally diagnosed as Binder phenotype, and discuss their postnatal diagnoses. METHODS: Ultrasonographic detailed measurements in 2D and 3D were done on the 8 fetuses with Binder profile, and were compared with postnatal phenotype. RESULTS: All fetuses have an association of verticalized nasal bones, abnormal convexity of the maxilla, and some degree of chondrodysplasia punctata. The final diagnoses included fetal warfarin syndrome (one patient), infantile sialic acid storage (one patient), probable Keutel syndrome (one patient), and five unclassifiable types of chondrodysplasia punctata. CONCLUSION: This series demonstrates the heterogeneity of prenatally diagnosed Binder phenotype, and the presence of chondrodysplasia punctata in all cases. An anomaly of vitamin K metabolism, possibly due to environmental factors, is suspected in these mild chondrodysplasia punctata. We recommend considering early prophylactic vitamin K supplementation in every suspected acquired vitamin K deficiency including incoercible vomiting of the pregnancy.