Sensenbrenner Syndrome Presenting with Severe Anorexia, Failure to Thrive, Chronic Kidney Disease and Angel-Shaped Middle Phalanges in Two Siblings

Abstract

Sensenbrenner syndrome is a very rare autosomal recessive disorder caused by variants in genes involved in the functional development of primary cilia. Typical clinical manifestations include craniofacial and skeletal abnormalities, hence the alternative name cranioectodermal dysplasia. Chronic kidney disease due to progressive tubulointerstitial nephritis (nephronophthisis) has been described in these patients. The authors present 2siblings with severe anorexia, failure to thrive, chronic kidney disease, and angel-shaped middle phalanges. Two previously described variants p.(Leu641*) and p.(Asp841Val) were identified in the WDR35 gene which is most commonly affected in this condition. Analysis of all coding exons of the GDF5 gene was normal. This is the first report of Sensenbrenner syndrome presenting with severe anorexia and failure to thrive at early age. Angel-shaped middle phalanges in the absence of the GDF5 variant may represent an overlapping phenotypic manifestation of ciliopathy.

Established Facts

• Sensenbrenner syndrome is a very rare autosomal recessive disorder. Significant renal impairment due to progressive tubulointerstitial nephritis (nephronopthisis) may be present at a very early age.

• Angel-shaped phalangoepiphyseal dysplasia has been typically described in patients with variants in the growth differentiation factor 5 (GDF5) gene rather than WDR35 gene.

Novel Insights

• This is the first report of Sensenbrenner syndrome (WDR35 variant) presenting with severe anorexia and failure to thrive.

• Angel-shaped middle phalanges have not been described in patients with Sensenbrenner syndrome and may represent an overlapping phenotypic manifestation of ciliopathy.

Introduction

Sensenbrenner syndrome is a very rare autosomal recessive ciliopathy. More than 60 patients have been described in the literature [Sensenbrenner et al., 1975]. Variants in 6 genes including IFT122, IFT43, IFT140, IFT52, WDR19, and WDR35 have been identified in patients with Sensenbrenner syndrome so far [Gilissen et al., 2010; Walczak-Sztulpa et al., 2010, 2020]. Mutations in WDR35 and IFT122 are the most common cause of cranioectodermal dysplasia (CED). All of these genes encode proteins that are important in intraflagellar transport [Ruiz-Perez et al., 2007; Walczak-Sztulpa et al., 2020].

Typical clinical manifestations of Sensenbrenner syndrome include dolichocephaly, narrow thorax, rhizomelic micromelia, facial dysmorphia (epicanthic folds, hypotelorism), brachydactyly, syndactyly, abnormal fingernails and toenails as well as dental anomalies [Sensenbrenner et al., 1975]. Chronic kidney disease with progressive tubulointerstitial nephritis (nephronopthisis) may be present at a very early age [Obikane et al., 2006]. Other rare manifestations include hepatic cysts with fibrosis [Zaffanello et al., 2006], recurrent lung infections and respiratory failure [Tamai et al., 2002], heart defects, and ocular anomalies (retinitis pigmentosa) [Eke et al., 1996; Costet et al., 2000]. Most affected children have normal neurological development, though cases with intellectual disability have been described in the literature [Fehrenbach et al., 2014; Li et al., 2015]. Prognosis of CED mainly depends on renal and liver insufficiency [Tamai et al., 2002; Obikane et al., 2006].

Angel-shaped phalangoepiphyseal dysplasia (ASPED) is a rare autosomal dominant form of acromelic dysplasia, characterized by a metacarpophalangeal pattern profile mainly affecting the first metacarpals and middle phalanges of second, third, and fifth digits which all appear short; epiphyseal changes in the hips; abnormal dentition, and delayed bone growth [Giedion et al., 1993]. The diagnosis of ASPED is confirmed by the presence of typical features on skeletal X-ray [Holder-Espinasse et al., 2004]. It is caused by defects in the growth differentiation factor 5 gene (GDF5) critical for bone growth and cartilage and joint morphogenesis. Angel-shaped middle phalanges have not been described in patients with Sensenbrenner syndrome.

Clinical Report

Patient 1

The male patient was born after a second uneventful pregnancy to consanguineous parents (they are third cousins) at 38 weeks with a birth weight of 4,130 g (50th centile), length 51 cm (97th centile), and a head circumference of 37 cm (97th centile). Postnatal adaptation was normal. Typical skeletal abnormalities of CED including osteochondrodysplasia, dolichocephaly, prominent forehead, low-set ears, short neck, narrow thorax, brachydactyly, syndactyly of the second and third toes, dysmorphic facial features (epicanthic folds, hypotelorism), and hypospadias were present immediately after birth (Fig. 1 a,b). X-ray showed angel-shaped middle phalanges of the II–V fingers of both hands (Fig. 1e). Postnatal renal ultrasound showed normal-sized kidneys with increased parenchymal echogenicity. The boy developed a transient episode of acute kidney injury with maximum creatinine of 108 μmol/L (reference range 23–68 μmol/L) which resolved completely. Within the first years of life, he suffered from severe anorexia, vomiting, and failure to thrive. At the age of 1 year, his weight was 9,340 g (25th centile) and length 75 cm (25th centile). Dentition was delayed and his teeth were small. At the age of 4 years, he developed hypertension with maximum systolic blood pressure of 135 mmHg. Renal biopsy at the age of 9 years confirmed tubulointerstitial nephritis with a moderate degree of chronic changes in renal parenchyma. At 11 years of age, his weight was 32.5 kg (10th centile) and length 143.5 cm (25th centile). He was treated for hypertension and chronic kidney disease (creatinine 210 μmol/L; reference range 23–68 μmol/L). His urine output and dipstick were normal. The follow-up ultrasound showed normal-sized kidneys with increased parenchymal echogenicity. He showed normal neurodevelopment. Recurrent respiratory infections (rhinosinusitis) were observed. Ciliary motility measured using Cilial Analysis software (LabVIEW^TM) [Hargas et al., 2011] was reduced with a beat frequency of 5.6 Hz (normal value 7–12 Hz).

Fig. 1.

a, b Dysmorphic features (osteochondrodysplasia, dolichocephaly, prominent forehead, low-set ears, short neck, narrow thorax, brachydactyly, syndactyly of the second and third toes, epicanthic folds, hypotelorism) in patient 1 at the age of 11 years. c, d Patient 2 at the age of 3 years with angel-shaped middle phalanges in digits II–V of both hands. e X-ray of the hand, patient 1.

Patient 2

Sibling of patient 1 was born after a third uneventful pregnancy at 41 weeks. His birth weight was 4,470 g (90th centile), length 50 cm (10th centile), and he had a head circumference of 38.5 cm (97th centile). Postnatal adaptation was normal. Typical skeletal abnormalities of CED were diagnosed antenatally. Osteochondrodysplasia, dolichocephaly, prominent forehead, low-set ears, short neck, narrow thorax, brachydactyly, syndactyly of the second and third toes, and dysmorphic facial features (epicanthic folds, hypotelorism) were present (Fig. 1c, d). X-ray confirmed angel-shaped middle phalanges of the II–V digits of both hands. Postnatal renal ultrasound showed normal-sized kidneys with increased parenchymal echogenicity. The dominant clinical features within the first months of life were anorexia and vomiting. A nasogastric tube was inserted due to failure to thrive at the age of 2 months. Dentition was delayed and his teeth were small. At the age of 3 years, his weight was 12 kg (<3rd centile) and height 90 cm (3rd centile). Renal function (creatinine 47 μmol/L; reference range 23–68 μmol/L) and blood pressure (90/42 mmHg) were normal. The follow-up ultrasound showed normal-sized kidneys with increased parenchymal echogenicity. The patient showed normal neurodevelopment. Ciliary motility measured using Cilial Analysis software (LabVIEW^TM) [Hargas et al., 2011] was normal with a beat frequency of 7.5 Hz (normal value 7–12 Hz).

Genetic Analysis

Screening of 4 genes (WDR35, IFT122, WDR19, IFT43) was performed in patient 1 using a next-generation sequencing method (NextSeq system; Illumina, San Diego, CA, USA). Entire coding and splice-relevant regions of the genes were analyzed. Two variants in heterozygous state were detected in the WDR35 gene (NM001006657.1). The c.1922T>G (p.Leu641*) variant in exon 18 is listed in the population databases dbSNP (rs199952377) and gnomAD (0.020%), and based on clinical studies listed in the ClinVar (ID: 65,619) database as a pathogenic variant. The c.2522A>T (p.Asp841Val) change in exon 22 is not listed in the dbSNP or gnomAD databases. However, based on clinical studies, ClinVar (ID: 65,619), this variant is defined as pathogenic. Examination of the WDR35 gene was performed in patient 2 using a next-generation sequencing method (NextSeq system, Illumina). The presence of both variants was confirmed. Segregation analysis revealed that the p.(Leu641*) variant was paternally inherited, and the p.(Asp841Val) change was maternally inherited. This variant was also identified in 2 healthy siblings (older brother and younger sister).

In both patients, the coding regions of GDF5 were analyzed by Sanger sequencing on ABI3500 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). All coding exons of the GDF5 gene were analyzed. The primers were designed to encompass, in particular, exons 3 and 4 together with their flanking intron-exon junctions. The sequencing results data were evaluated using Chromas software and compared with the corresponding reference sequence (NC_000020.11). No causal variants were identified.

Discussion

Herein, we report 2 siblings with Sensenbrenner syndrome with anorexia and failure to thrive throughout infancy. This feature has not been described in the literature before. As the main causes of anorexia have been ruled out (cystic fibrosis, celiac disease), we hypothesize that anorexia could be a manifestation of Sensenbrenner syndrome present at an early age.

Interestingly, both siblings have phenotypic manifestation of Sensenbrenner syndrome and angel-shaped middle phalanges. Sensenbrenner syndrome and ASPED have several features in common. Abnormal dentition and delayed bone growth, acromelic dysplasia, characterized by a metacarpophalangeal pattern profile was not observed in patients with Sensenbrenner syndrome. The diagnosis of CED is obvious in the herein reported patients. However, it is sometimes difficult to make a definitive diagnosis because the clinical signs of skeletal ciliopathies overlap [Handa et al., 2020]. In addition, phenotypic features are variable even in patients with the same mutations. In patients described in this clinical report, 2 heterozygous mutations in the WRD35 gene, a nonsense mutation p.(Leu641*) and a missense mutation p.(Asp841Val), were detected. These variants are listed in the ClinVar database. Both variants have previously been described in patients with Sensenbrenner syndrome [Hoffer et al., 2013; Li et al., 2015; Walczak-Sztulpa et al., 2017, 2018, 2020, 2021]. Walczak-Sztulpa et al. [2017] presented intrafamilial variability in siblings with these variants. It contributes to the hypothesis that additional mutations in other genes (“genetic load”) can modulate the clinical manifestation and explain inter- and intrafamilial phenotypes. On the other hand, there are also nongenetic factors that may influence expression of relevant genes [Bredrup at al., 2011; Arts and Knoers, 2013]. Observed angel-shaped middle phalanges may represent an overlapping phenotypic manifestation of ciliopathy. We hypothesize it could also be a consequence of mutation in another gene responsible for proper morphogenesis of bones, cartilage, and joints. Whole-exome sequencing could provide an answer to this hypothesis.

Since both patients are compound heterozygotes for the WDR35 mutations, it is obvious that inherited alleles are not identical by descent, although their parents are distant relatives; they are third cousins (Fig. 2). The risk of the offspring of third cousins is comparable to the general population, as the probability of carrying identical mutations decreases with the decreasing degree of relatedness [Shawky et al., 2013].

Fig. 2.

Pedigree of the family and relationships in individual generations.

According to the literature, many cilia-associated proteins found in primary cilia are also found in motile cilia [Fliegauf et al., 2006; Driscoll et al., 2008]. These are primarily proteins needed for the ciliary base such as the transition zone or basal bodies or proteins important for intraflagellar transport [Kempeneers and Chilvers, 2018]. According to observations by Li et al. [2015], WDR35 deficiency disrupted ciliogenesis in the airway. Ciliogenesis was largely blocked and few cilia formed exhibiting slow dyskinetic ciliary motion. Therefore, we evaluated the ciliary beat frequency. Only patient 1 had a reduced ciliary beat frequency. There may be factors other than WDR35 affecting ciliary function which have not been described to date. It is known that chronic kidney disease is associated with ciliary dysfunction. This is supported by findings from Kucur et al. [2016] that chronic kidney disease may be one of the risk factors for mucociliary clearance dysfunction.

Summary

Ciliogenesis is rather complex process that can be influenced by several factors, not all of which are known to date. The phenotype of various ciliopathies may overlap. Sensenbrenner syndrome is a rare primary ciliopathy. The clinical picture is easily recognizable in most patients. New phenotypic manifestations described here (anorexia, failure to thrive, angel-shaped middle phalanges) may occur.

Statement of Ethics

The parents gave their consent to publish this case report. The study protocol was part of a clinical study approved by the Ethics Committee of the Jessenius Faculty of Medicine, Comenius University in Bratislava, Slovakia (study No. EK 1/2020).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

There are no sources of funding that need to be reported.

Author Contributions

Each author participated fully in this case report. All authors concur with this submission and approved the final version of the revised manuscript.