Prenatal phenotype of Wolf-Hirschhorn syndrome: A case series and literature review.

OBJECTIVE: Wolf-Hirschhorn syndrome (WHS) is a congenital malformation syndrome with poor prognosis. It is associated with a heterozygous deletion of chromosome 4p16.3. Adequate knowledge of prenatal phenotypes and proper prenatal counseling are essential for intrauterine diagnosis. METHOD: We retrospectively analyzed 11 prenatal cases of WHS diagnosed using low-depth whole-genome sequencing (copy number variation sequencing) performed at our hospital from May 2017 to September 2022 and reviewed their prenatal ultrasound reports in detail. We also analyzed WHS cases (including prenatal and postnatal) with abnormal prenatal ultrasound findings in the published literature over the past 20 years. RESULTS: Among the 11 fetuses with a prenatal diagnosis of WHS in our hospital, four cases showed abnormal prenatal ultrasound findings, including shrunken kidneys, ventricular septal defect, a small stomach, fetal growth restriction (FGR), enlarged posterior fossa, and soft ultrasonic markers. Our four cases were combined with 114 published WHS cases with prenatal ultrasound abnormalities from other medical institutions. Of the 118 cases, 59.3% (70 of 118) were multiple malformations. The most frequent ultrasound features observed in all 118 cases were FGR (76.3%, 90 of 118), followed by facial anomalies (28.8%, 34 of 118), central nervous system anomalies (27.1%, 32 of 118), and soft ultrasound markers (23.7%, 28 of 118). Other less common phenotypes included cardiac anomalies (19.5%, 23 of 118), genitourinary anomalies (19.5%, 23 of 118), increased NT/NF (12.7%, 15 of 118), skeletal anomalies (11.9%, 14 of 118), a single umbilical artery (10.2%, 12 of 118), gastrointestinal anomalies (9.3%, 11 of 118), oligohydramnios (8.5%, 10 of 118), cystic hygroma (5.1%, six of 118), hydrops/pleural effusion/ascites (2.5%, three of 118), and polyhydramnios (2.5%, three of 118). CONCLUSION: This study improved our understanding of the prenatal presentation of WHS by analyzing prenatal ultrasound abnormalities. The timely identification of prenatal ultrasound abnormalities can provide accurate consultation for pregnant women, improve the prenatal detection of WHS, and enable early prenatal management and intervention of WHS.

Prenatal sonographic findings in confirmed cases of Wolf-Hirschhorn syndrome.

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a common genetic condition and prenatal diagnosis is difficult due to heterogeneous expression of this syndrome and rather non-specific ultrasound findings. Objective of this study was to examine the prenatal ultrasound findings in fetuses with Wolf-Hirschhorn syndrome (WHS). METHODS: Retrospective assessment of 18 pregnancies that were seen at three tertiary referral centers (Universities of Bonn, Tuebingen and Nuernberg / Germany). Findings of prenatal ultrasound examinations, genetic results and outcome were compared. Additionally, findings of our study were compared to previous small case series from the literature and then compared to data on postnatal frequencies and abnormalities in affected patients. RESULTS: Median gestational age at the time of examination was 23 + 1 weeks' (range: 13 + 4 to 29 + 1 weeks') with female-to-male ratio of > 2.5:1. Most frequent ultrasound findings were facial abnormalities, symmetric IUGR and microcephaly that presented in 94.4, 83.3 and 72.2% of cases, respectively. The combination of microcephaly and hypoplastic nasal bone was a particularly characteristic finding. Growth retardation presented in all fetuses > 20 weeks, but not below. Other frequent abnormalities included cardiac anomalies in 50 and single umbilical artery (SUA) in 44.4% of fetuses. CONCLUSION: WHS should be considered in the presence of symmetric IUGR together with microcephaly, hypoplastic nasal bone and facial abnormalities on prenatal ultrasound. Genetic testing by chromosomal microarray analysis (CMA) is strongly recommended in this context.

Hip displacement in Wolf-Hirschhorn syndrome: Report on three cases and review of associated musculoskeletal pathologies.

Wolf-Hirschhorn syndrome is a rare genetic disease caused by a chromosomal deletion of the distal short arm of Chromosome 4. It is associated with multisystem abnormalities, including delayed growth, characteristic facial features, epilepsy, and skeletal abnormalities. We report three patients who developed hip displacement, and describe the occurrence of delayed and nonunion in patients who underwent corrective proximal femoral osteotomy for hip displacement. We also performed a literature review identifying common musculoskeletal presentations associated with the condition. Patients with Wolf-Hirschhorn Syndrome are at risk of hip displacement (subluxation), and we would advocate annual hip surveillance in this patient group.

Risk of hepatic neoplasms in Wolf-Hirschhorn syndrome (4p-): Four new cases and review of the literature.

Wolf-Hirschhorn syndrome (WHS) is a rare contiguous gene deletion disorder characterized by distinctive craniofacial features, prenatal/postnatal growth deficiency, intellectual disability, and seizures. Various malformations of internal organs are also seen. Neoplasia has not been documented as a typical feature of WHS. We review the three prior reports of hepatic neoplasia in WHS and add four previously unreported individuals. We propose that, in the context of the rarity of WHS, these seven cases suggest that hepatocellular neoplasia may be a feature of WHS.

Prenatal diagnosis of Wolf-Hirschhorn syndrome: from ultrasound findings, diagnostic technology to genetic counseling.

PURPOSE: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome due to terminal chromosome 4p deletions. We explored prenatal diagnosis of WHS by ultrasound as well as karyotype and single nucleotide polymorphism array (SNP array) to characterize the structural variants of WHS prenatally. METHODS: Ten prenatal cases of WHS were evaluated for the indication of the invasive testing, the ultrasound features, and cytogenetic and microarray results. RESULTS: Eight cases were diagnosed by karyotyping and SNP array, while two cases were detected only by SNP array. Combining our cases with 37 prenatal cases from the literature, the most common sonographic features were IUGR (97.7%) and typical facial appearance (82.9%). Other less common phenotypes included renal hypoplasia (36.2%), cardiac malformation (29.8%), cleft lip and palate (25.5%), cerebral abnormalities (25.5%), skeletal anomalies (21.3%), and increased nuchal translucency/nuchal fold thickness (NT/NF) (19%). CONCLUSIONS: The most common intrauterine phenotypes of WHS were severe IUGR and typical facial appearance with other less consistent ultrasound findings. Noninvasive prenatal testing (NIPT) is one very promising screening tool for WHS. SNP array can improve diagnostic precision for detecting WHS, especially for the cryptic aberrations that cannot be identified by the traditional karyotyping. Ectopic kidney may be a previously unrecognized phenotype of WHS.

Prenatal diagnosis of Wolf-Hirschhorn syndrome: Ultrasonography and molecular karyotyping results.

OBJECTIVE: To present the experience on prenatal diagnosis of Wolf-Hirschhorn syndrome (WHS) to further delineate the fetal presentation of this syndrome. STUDY DESIGN: This was a retrospective analysis of ten pregnancies with fetal WHS identified by chromosomal microarray (CMA). Clinical data were reviewed for these cases, including maternal demographics, indications for invasive testing, sonographic findings, CMA results and pregnancy outcomes. RESULTS: Three cases were diagnosed at the first trimester because of an increased NT or cystic hygroma. The remaining seven cases were identified at late gestation for abnormal ultrasound findings. CMA revealed 4p deletions to be terminal in all of the ten cases. Deletion sizes ranged from 2.05 to 19.02 Mb. CONCLUSION: Prenatal findings such as increased NT, severe and early onset intrauterine growth retardation, and renal dysplasia or oligohydramnios should warrant the diagnosis of WHS and invasive testing using CMA.

Crecimiento intrauterino restringido como síntoma guía para el diagnóstico genético prenatal del síndrome de Wolf-Hirschhorn en gestación gemelar bicorial biamniótica / Restricted Intrauterine Growth as a Guiding Symptom for Prenatal Genetic Diagnosis of Wolf-Hirschhorn Syndrome in Bicorial Diamniotic Twin Gestation

El síndrome de Wolf Hirschhorn, también conocido como monosomía del brazo corto del cromosoma 4 (4p) o síndrome 4p-, es una rara enfermedad genética descrita por primera vez en el año 1961 por los doctores Cooper y Hirschhorn. El objetivo del trabajo es presentar un caso clínico sobre el síndrome de Wolf-Hirschhorn, que es un trastorno genético raro y aún bastante desconocido que cursa con múltiples anomalías morfológicas congénitas, así como con un retraso neurológico e intelectual de grado variable. La prevalencia de este síndrome es extremadamente baja, teniendo en cuenta que la cifra puede estar infraestimada, dada las pérdidas gestacionales precoces y la dificultad en el diagnóstico prenatal. Reportamos el caso de una paciente con gestación gemelar bicorial biamniótica tras un ciclo de FIV-ICSI, en el que al segundo gemelo se diagnosticó un Síndrome de Wolf-Hirschhorn, luego del estudio por una discordancia de pesos estimados y crecimiento intrauterino restringido de este segundo feto. El patrón clásico de presentación clínica se caracteriza por el desarrollo de alteraciones craneofaciales importantes, retraso en el crecimiento normal tanto prenatal como posnatal y deficiencia mental e intelectual de grado variable. El diagnóstico prenatal debe ser realizado por expertos. Puede sospecharse por un crecimiento intrauterino restringido, ya que se da en 80-90 por ciento de los fetos con esta patología. Una vez diagnosticado, se recomienda el estudio genético de los padres, dado que hasta 15 por ciento de los progenitores pueden padecer un reordenamiento cromosómico equilibrado en el brazo corto del cromosoma 4(AU)

Wolf Hirschhorn syndrome, also known as monosomy of the short arm of chromosome 4 (4p) or 4p-syndrome, is a rare genetic disorder first described in 1961 by doctors Cooper and Hirschhorn. The prevalence of this syndrome is extremely low, taking into account that the figure may be underestimated given the early gestational losses and the difficulty in prenatal diagnosis. The objective of the study is to present a clinical case of Wolf-Hirschhorn syndrome, presenting with multiple congenital morphological anomalies, as well as a neurological and intellectual retardation of variable degree. We report the case of a patient with a bicorial biamniotic twin gestation after a cycle of IVF-ICSI. The second twin was diagnosed with a Wolf-Hirschhorn syndrome, after performing the corresponding study due to a discordance of estimated weights and restricted intrauterine growth of this second fetus. The development of important craniofacial alterations, delay of normal prenatal and postnatal growth, and mental and intellectual deficiency of variable degree characterize the classic clinical presentation. Experts must make prenatal diagnosis. Wolf-Hirschhorn syndrome can be suspected by a restricted intrauterine growth, as it occurs in 80-90 percent of fetuses with this pathology. Once diagnosed, the genetic study of the parents is recommended, since up to 15 percent of the parents can suffer a balanced chromosomal rearrangement in the short arm of chromosome 4(AU)

[The Wolf-Hirschhorn Syndrome]. / Das Wolf-Hirschhorn Syndrom.

Wolf-Hirschhorn syndrome (WHS) represents a complex developmental disorder characterized by craniofacial dysmorphism, short stature, hypotonia, psychomotor retardation and seizures caused by a terminal deletion of the short arm of chromosome 4. Depending on the extent of the deletion, variable midline defects, abnormalities of the skeletal or urogenital system as well as the central nervous system are observed. Approximately 1/3 of the infants will die in the first year of life even though survival for more than 30 years has been reported. Due to current high quality standards of ultrasonography, WHS can often be diagnosed prenatally. We present a clinical case and provide an overview of the current literature.

Detection of recurrent 4p16.3 microdeletion with 2p25.3 microduplication by multiplex ligation-dependent probe amplification and array comparative genomic hybridization in a fetus from a family with Wolf-Hirschhorn syndrome.

OBJECTIVE: We present prenatal diagnosis, genetic counseling, and molecular cytogenetic features of familial recurrence of Wolf-Hirschhorn syndrome (WHS). MATERIALS AND METHODS: A 31-year-old woman was referred to a hospital at 24 weeks of gestation because of abnormal ultrasound findings in the fetus. Her first child was a boy who had growth retardation, mental defect, and a distinctive facial appearance. Based on the conventional cytogenetic analysis, the combined use of multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH) facilitated the prenatal diagnosis and genetic counseling in the fetus. Results of the standard G-banging karyotype analysis of the fetus, the parents, and the boy were normal. RESULTS: The MLPA analysis revealed the same 4p microdeletion accompanied by 2p microduplication in the fetus and the boy. The aCGH analysis revealed a 3.57-Mb 4p16.3 microdeletion or arr [hg19] 4p16.3 (71,552-3,636,893) x1 in the fetus and a 3.29-Mb 4p16.3 microdeletion or arr [hg19] 4p16.3 (71,148-3,360,737) x1 in the boy. The 3.57-Mb 4p16.3 microdeletion encompassed 39 OMIM genes. The 3.29-Mb 4p16.3 microdeletion encompassed 36 OMIM genes. They both included LETM1 and WHSC1. The 2p25.3 microduplication was smaller than 666 kb and encompassed only one OMIM gene, ACP1. CONCLUSION: The combined use of MLPA and aCGH is an effective way to diagnose recurrent WHS. Although WHS is typically caused by a de novo deletion, prenatal diagnosis and genetic counseling are necessary in the next pregnancy in families that have suffered such cases.