Rare association of Klippel-Feil syndrome with situs inversus totalis and review of the genetic background

Abstract

Klippel-Feil syndrome (KFS) is a rare congenital anomaly in forming the cervical vertebrae resulting in the fusion of two or more of the vertebrae. KFS is associated with many congenital anomalies, some of which are common and well known. Here, we report a child with an extremely rare association of KFS with situs inversus totalis (SIT). Both KFS and SIT are genetically heterogeneous and their co-occurrence suggests a high possibility of sharing the same underlying causative agent. Here, we review the genetic background that is known for these two conditions in the literature.

Background

Klippel-Feil syndrome (KFS) is a rare anomaly characterised by congenital fusion of the vertebrae due to the failure of cervical somites to segment during the early weeks of gestation. It ranges from the fusion of only two bodies of the vertebrae to the fusion of multiple bodies. KFS involved vertebral bodies tend to be flat with a hypoplastic or absent disc. It has been estimated that KFS occurs in approximately 1:40 000–42 000 births.¹ Many KFS associated anomalies have been reported, including atlantoaxial subluxation, cervical ribs craniovertebral junction anomalies, scoliosis, sprengel deformity, facial asymmetry, Poland anomaly, synkinesis, cleft palate, deafness, facial palsy, otolaryngeal structures abnormalities, ptosis, congenital heart disease, genitourinary anomalies, brain stem anomalies, Arnold Chiari I malformation, congenital cervical stenosis, adrenal aplasia and agenesis of lungs and gall bladder.^1–7

Case presentation

A 10-year-old boy was diagnosed with situs inversus totalis (SIT) at the age of 3 years after a routine child check-up (figure 1). He had an uneventful perinatal history with normal vaginal full term delivery. He had met all his developmental milestones. He is a second child of non-consanguineous parents. He has two male siblings. He and his eldest brother have pes planus with valgus deformity of both foots. No other anomaly was found in his brothers.

Figure 1.

Chest and upper abdomen X-ray for the child when he was 3 years old showing dextrocardia (black arrow) and situs inversus totalis (white arrow is pointing to the stomach shadow and yellow arrow is pointing to the liver shadow).

At the age of 3 years old, he was referred to the paediatric orthopaedics clinic after the mother noticed that her child had a deviated neck to the right with restriction of neck movement and deformed upper back. However, his deformity was not restricting his daily activity and he was asymptomatic with no neurological deficit.

Investigations

Investigation with C-spine CT and whole subsequent spine MRI revealed segmentation and fusion abnormalities involving C1–C3, a dysplastic dens with a fusion of the body of axis bone with C3 forming a butterfly vertebra, and widening of the atlantoaxial space measuring 0.73 cm (figures 2 and 3). The craniovertebral junction was normal. There were bilateral bony cervical ribs and syringohydromyelia of D5–D9 measuring 4.4×0.7 cm (figure 4). Further investigation showed right-sided mild hydronephrosis and no cardiac anomaly.

Figure 2.

CT scan for cervical spine of the patient at age of 3 years: C1, 2 and 3 abnormal segmentation and fusion (black arrow). C7 bilateral cervical ribs (white arrow).

Figure 3.

MRI T1 for Cervical spine of the patient at age of 3 years: A dysplastic dens (white arrow) and abnormal segmentation and fusion of upper cervical spine with a hypoplastic intervertebral disc (yellow arrow).

Figure 4.

Sagittal views MRI T2 for whole spine and thoracic spine showing syringohydromyelia of D5–D9 (red arrow).

Outcome and follow-up

He is now 10 years old and on regular follow-up for these abnormalities since the age of three. Clinically, he was complaining of neck pain on occasions with stable restriction of neck movement. The subsequent MRI showed the stability of the spinal deformity. He had no history of recurrent infections or signs of immune-deficiency.

Discussion

Most KFS cases are de novo and the familial types are rare.^{1 8} Therefore, we believe that our case is due to a single sporadic genetic mutation that resulted in this extremely rare association. The familial types reported in the literature are mostly autosomal dominant, while the rest are autosomal recessive.^{9 10} Four genes have been documented as a causative factor in KFS, and based on these, four genetic types of KFS have been described.¹⁰ The most commonly mutated gene in KFS is growth differentiation factor 6 GDF6, located in 8q22.1 with Gene Locus MIM number (601147). This gene is important in bones, joints, neurons and eye development.^{6 10 11} GDF6 is inherited as autosomal dominant but many sporadic cases have also been reported.^{6 12} The second gene is MEOX1 and is located in 17q21.31 with the gene locus MIM number (600147). It has a vital role in the segmentation of the somites in embryos and forming the skull base and craniocervical joints.¹¹ MEOX1 mutations are inherited as autosomal recessive, and only two studies have documented its mutation in KFS cases.^{13 14} The third gene is GDF3 and is located in 12p13.31 with gene locus MIM number (606522). Like GDF6, GDF3 has an important role in bone and eye formation.¹⁵ It has autosomal inheritance.¹¹ Only one study concluded that GDF3 mutation could result in KFS.¹⁵ MYO18B is the fourth gene and its location is in 22q12.1 with gene locus MIM number (607295). This gene is vital for both muscle and bone development. MYO18B is inherited in an autosomal recessive manner. Mutation of this gene is reported in only one study of two unrelated families with KFS.⁸ Patients with this gene are more likely to develop myopathy and dysmorphic facial features.^{11 16} Currently, these are the only known genes implicated in KFS. However, many patients with KFS fail to show a mutation in any of these four genes, suggesting another unknown causative gene.⁸

SIT is a mirror reversal of the normal asymmetrical arrangement of the internal organs. It has an estimated prevalence of 1 in 10 000 birth, most of whom has a complex cardiovascular malformations.¹⁷ SIT can occur in combination with primary ciliary dyskinesia (PCD), a recessive genetic disorder that involves mutations that disrupt motile cilia, resulting in symptoms such as chronic bronchitis, inflamed or infected sinuses and male infertility.^{17 18} PCD is known to be a recessive phenotype for which at least 30 different genes have already been identified and hence most of the patients of SIT with PCD have a known genetic cause for their condition.^{17 18} Our patient does not have symptoms related to PCD suggesting SIT without PCD as the condition in three-quarters of people with SIT, and the causes of their SIT remain largely unknown.¹⁸ Only few genes have been reported to be involved in SIT without PCD among which ZIC3 gene is the first one to identify and the best understood genetic cause with x-linked inheritance.¹⁷ Others are CCDC11, CFAP52, NME7 and PKD1L1.¹⁸ In their series of 15 patients with SIT, Postema et al reported six subjects with PCD and all had likely recessive mutations in genes already known to cause SIT with PCD. While, the genetic cause was clear only in four out of nine patients with SIT without PCD.¹⁸ However, with over 100 candidates genes identified through animal models of left-right patterning defects, it is likely that significant genetic heterogeneity will be found in human SIT.¹⁷

In the literature, we could find only two cases of KFS with SIT tested for the causative gene. The first one was conducted by Chacón-Camacho et al who reported a case of KFS with situs inversus that was investigated for GDF1, GDF3 and GDF6 as causal genes. The authors could exclude these three genes from causing this rare association.⁸ Karaca et al identified a homozygous frame shift mutation in RIPPLY2, a gene shown to play a crucial role in somitogenesis. Their data confirmed RIPPLY2 as a noval gene for autosomal recessive KFS, and in addition from the mechanistic standpoint they suggested that mutations in RIPPLY2 could also lead to SIT.¹⁹ Unfortunately, genetic investigation of our case is beyond our capabilities.

Learning points.

• The association of Klippel-Feil syndrome (KFS) with situs inversus is rare and their underlying genetic pathology is complicated and little investigated.

• Clinical history of such association tends to be benign and stable with minimal impact on patient’s daily life.

• This association gives evidence to investigate KFS patients for known genes that are involved in lateralisation.