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Revista chilena de pediatría

versión impresa ISSN 0370-4106

Rev. chil. pediatr. vol.90 no.2 Santiago abr. 2019

http://dx.doi.org/10.32641/rchped.v90i2.779 

CLINICAL CASE

Klippel-Feil autosomal dominant syndrome: a malformation of vertebral segmentation

Víctor Hugo Guapi Nauñay1 

Iván Alejandro Martínez Carvajal2 

1 Department of Neonatology. Genetic Counselling. General Hospital "Luis G Dávila", Tulcán City, Ecuador.

2 Department of Radiodiagnosis. General Hospital "Luis G Dávila", Tulcán City, Ecuador.

Abstract:

Introduction:

Klippel-Feil syndrome is a highly heterogeneous complex skeletal disorder characterized by the con genital fusion of two or more cervical vertebrae. The classic clinical triad consists of a short neck, low hairline, and neck movements limitation. The associated mutations are located in the loci of the GDF3 gene (chromosome 12pl3.31), GDF6 (chromosome 8q22.1), and MEOXI (chromosome 17q21.31).

Objective:

To describe the clinical-radiological findings and pedigree of a patient with Klippel-Feil syndrome.

Clinical case:

A 5-year-old patient with short neck, low posterior hairline, and limitation of lateral movements. The cervical flexion and extension radiographs showed fusion blocks between C1-2-3, C4-5, and C6-7. The chest CT scan showed multiple hemivertebrae in the upper third of the thoracic vertebrae corresponding to ribs 1-tv. The karyotype was normal, 46, XX. Reduced penetrance was present in five of the family members. The fusion of C2-3 was present in four members and one individual had low fusion in C5-6. Three of the five affected individuals had a fusion between the capitate and the hamate bone.

Conclusion:

The malformation of congenital vertebral segmentation is a case of interest since it is an uncommon diagnosis in the pediatric age and whose clinical suspicion can be generated from the clinical examination, radiological study com plemented with the pedigree interpretation in Mendelian inheritance disorders, allowing to provide opportunely genetic counseling to the family.

Keywords: Klippel-Feil syndrome; congenital abnormalities; cervical vertebrae; scoliosis

Introduction

Klippel-Feil Syndrome (KFS) (OMIM# 118100) is a highly heterogeneous complex skeletal dysplasia characterized by the congenital fusion of two or more cervical vertebrae1. It is caused by a failure in the nor mal vertebrae segmentation during the fourth week of gestation2. The classic clinical triad consists of a short neck, low hairline, and neck movement limitations. Only 34-74% of diagnosed cases have classical clini cal manifestations3. The estimated incidence is 1 per 40,000 to 42,000 births worldwide and is most preva lent in females with a 1.5/1 ratio4.

There are four KFS types5 which are type I, classic single C1 fusion (autosomal recessive); type II, C2-C3 synostosis, cervical, thoracic, and lumbar fusion, and variable expression among a family (autosomal dominant); type Ill, isolated cervical fusion (recessive), and type IV, fusion in cervical vertebrae (probably linked to the X chromosome) classified according to differences in vertebral synostosis in specific regions and inheritan ce pattern. In Ecuador, the four described cases were from the Genetics of Paz-y-Miño (2014a) consultation6.

Mutations associated with autosomal dominant KFS syndrome7,8 are located in GDF3, GDF6, and MEOX1 genes. The GDF3 gene (is a growth differen tiation factor 3) of the family TGF-p/BMP (transfor ming growth factor-beta/bone morphogenetic pro tein), and mutations in this gene cause the Klippel-Feil Ill deformity. GDF6 (growth differentiation factor 6) is also of the TGF-p/BMP family and mutations in this gene cause KFS I deformity. The protein encoded by the MEOX1 gene (homeobox protein MOX-1) plays a role in somitogenesis and is specifically involved in the sclerotome formation9,10.

Pax genes also play an important role during verte brate embryogenesis, possibly by determining the tem porality and place of organs formation such as the bra in, eyes, ears, nose, spine, kidneys, and limb muscles.

Considering its genomic organization, domain se quences, and expression patterns, the Pax gene family has been classified into four subfamilies; family 1 con sists of genes Pax1 and Pax9, family 2 of genes Pax2, Pax5 and Pax8; family 3 of genes Pax3 and Pax7; and family 4 of genes Pax4 and Pax611.

During the fourth week of embryonic develop ment, the differentiation of somites takes place, where the sclerotome expresses the Pax1 transcription factor, which initiates the genes cascade that forms cartila ge and bone for the formation of vertebrae, ribs, and sternum2,10. The hemivertebra is caused by insufficient segmentation of two or more vertebrae12.

The objective of this research was to describe the clinical-radiological and genealogical findings of a pa tient with Klippel-Feil syndrome.

Clinical case

Female patient, only child of a couple with no his tory of consanguinity or endogamy who was referred at age 5 to the genetic service. She had seven prenatal controls, the mother had no history of consumption of alcohol or valproic acid during pregnancy. The patient was born by eutocic delivery of 38 weeks gestation ac cording to the date of last menstruation, with anthro pometry corresponded to a small-for-gestational-age term newborn, weight 2.030 g, height 39.5 cm, head circumference 29 cm, Apgar at 9 minutes and at 5 mi nutes, discharged after two days of life.

At one year of age, she was referred to Neuropedia trics due to right brachial plexus palsy, where she un derwent a CT scan of the skull which showed normal results. She had normal progression of developmental milestones, attending preschool education.

The genetic service admission exam highlighted normal intelligence. In the segmental examination, deviation of the head to the left side was observed; skull and face with high and wide forehead; midfacial hypoplasia; slightly arched eyebrows, long eyelashes, white corneas; wide, flattened nose with slight nasal filter; thick cheeks; slightly thick lips, normal occlu sion, and crooked teeth; retrognathia; prominent, low set and posteriorly-rotated left ear; short neck, low posterior hairline, and limited neck range of la teral motion. The posterior thorax showed right side scoliosis in the dorsal region, and small and promi nent scapulae in high position; the left anterior he- mithorax with elevation at the second and third costal cartilage; elbow, wrist, hands, and foot flexion restric tion. There were no clinical signs of spinal cord com pression (Figure 1).

Figure 1 lateral view of patient with 5 years old that note shortness of neck (a). Posterior view with lower hairline in addition sprengel's deformity to consist elevation of scapula (b)

Laboratory tests showed blood count, biochemical profile, and thyroid tests in normal range. Conven tional cytogenetic analysis, by lymphocytes culture obtained from peripheral blood with GTG-banding techniques (20 metaphases) showed normal fema le karyotype 46, XX. Flexion-Extension X-ray of the cervical region showed multiple blocked vertebrae with absence of intervertebral spaces between C1-C2- C3, C4-C5, C6-C7 (Figure 2). Wrist X-ray showed fu sion between the capitate and the hamate bone (not shown).

Figure 2 Laterals cervical radiographies (a y b) showing sinostosis of vertebral bodies C1-2-3, C4-5 and C6-7. a) Extension. b) Flexion. 

The CT-scan volumetric reconstruction findings included costal arches synostosis in the left hemithorax at the back end of I-IV, this one shorter in relation to the adjacent costal arches (Figure 3 a); costal arches synostosis in the right hemithorax in the middle third and back end of 1-in. There was no difference between them, and to a greater extent in the contralateral side (Figure 3b). ill short rib arch in relation to the IV one and absence of the Xii rib (Figure 3c).

Figure 3 3D Conputerized Re constructional format the bones of the thorax, anterior view whith absence of intercostal space back extreme to the costal angle: the left hemithorax I-IV (a) and the right hemithorax I-III (b) respectively. shorter costal arches sternales: left IV and right III, whith absence of the XII floatin rib homoside (c). I have far-off electronically the ster num and clavicular. 

In addition, it showed multiple non-segmented hemivertebrae of the thoracic vertebrae in the upper third (T1-T4) corresponding to ribs I-IV and verte bral wedges of T5-T6. Marked right scoliosis (Figure 3c).

Cardiological, ophthalmological, hearing, and ab dominal ultrasound evaluations were normal.

In addition to the clinical evaluation, the patient’s genealogy was made, defined as case III-5 (Figure 4). When interpreting the family genealogy, it was defi ned that the individuals (I-5, II-6, II-10, II-14, III- 5) presented compatible KFS symptomatology with probable autosomal dominant inheritance pattern, therefore, X-ray of the thoracic cervical spine was in dicated.

Figure 4 Klippel-Feil syndrome family pedigree. 

Considering the decrease in reproductive capacity and also the low prevalence of these defects, it is un likely that there is a union between parents (II-5 and II-6) affected by a mutation causing the same syndro me. To rule out this possibility, an X-ray of the tho racic cervical spine was performed at II-5, which was normal (not shown).

The I-5 cervical spine radiography showed a spi nous process fusion between C2-C3 with partial ossi fication between the vertebral bodies where the inter vertebral space is significantly narrow, with no carpal fusion (Figure 5a).

Figure 5 Vertebral cervical radiographs showed the intervertebral space is significantly narrow and spinous process fusion between:C2-3 patient I-5 (a), ii-10 (b) and ii-14 (c), respectively; C5-6 patiente ii-6 (d). X-ray of the carpometacarpal showed fusion between the capitate and hamate bone: The patiente ii-10 (e) and ii-14 (f), respectively. R, right; G, capitate; g, hamate. 

Patient II-6 (Figure 5d) presented spinous process fusion between C5-C6 and a significant decrease in the intervertebral space, and carpus bones (hamate) are also fused. Abdominal ultrasound showed normal kidney characteristics, as well as ureters and bladder without alterations. Audiological examination repor ted absence of pathology and conventional cytogenetic analysis, with G-Banding (20 metaphases) showed a karyotype 46, XX.

Patients II-10 and II-14, walked in small steps tou ching the floor because they cannot lift their legs while keeping them together from the knee up, as a result of the pyramidal tract involvement. Cervical spine ra diography identified spinous process fusion between C2-C3 and partial ossification between the vertebral bodies, with significant narrowing of the interverte bral space (Figures 5b and c). The wrist radiography showed fusion between the capitate and hamate bone (Figures 5e and f). They are currently being treated with physiotherapy.

The four maternal relatives (I-5, II-6, II-10, II-14) of the index case (III-5) were examined and evalua ted, including II-5 (Figure 4) using thoracic spine and carpal bone radiography, of the eight living maternal individuals. Five of the six evaluated showed at least significant narrowing of the intervertebral space bet ween C2-C3 or C5-C6.

The KFS was present in five members of the family (I-5, II-6, II-10, II-14, III-5). All affected individuals presented cervical spine fusion, four of them (I-5, II- 10, II-14, III-5) presented high fusions in C2-C3 and one (II-6), low fusion in C5-C6.

Out of the five individuals with vertebral involve ment, in only three (II-10, II-14, III-5) fusion between the capitate and hamate bone was found. None of the affected individuals of the family of patient III-5 in the three generations with this dominant genetic entity, it was observed vocal alteration associated with laryngeal cartilage malformations.

The research protocol was sent to the ethics com mittee for comment, review, and approval; allowing for the recording of index case data and their relatives with the results subsequently publication.

Discussion

Klippel-Feil syndrome is caused by a failure in the cervical vertebral segmentation with wide phenotypic variability, however, a common characteristic of these patients is the presence of cervical spine fusion in C2- C3 as a universal finding6.

Patient III-5 presented the classic KFS triad, with cervical spine fusion, short neck, and low posterior hairline, although only 34% of cases present the com plete triad, as well as limitation of arm flexion move ments. Currently, the patient has no clinical signs of spinal cord compression, with good prognosis. Pa rents, teachers, and the patient herself must be aware of avoiding trauma, physical activities that could injure the spinal cord with the devastating consequences that would imply13,14,15.

In addition to the various vertebral alterations, this is the first case in which synostosis of costal arches with KFS is described, demonstrated with CT scan and volumetric reconstruction of the thoracic cervical spine, exhibiting the need for imaging and cytogenetic stu dies in patients with vertebral fusion.

The patient III-5 presented the highest degree of severity, with multiple cervical blocked vertebrae (C1-C2-C3/C4-C5/C6-C7), and wrist radiography showed fusion in the carpus. All of these developmen tal defects occur due to haploinsufficiency (as a patho logical mechanism) possibly in some of the other genes such as Pax1 during embryogenesis, proposed by Mc- Gaughran (2003), by describing the importance in the specific regulation of cell proliferation position11.

The mother (II-6) had a less severe phenotype than the index case or other relatives, the reduced penetran ce could be explained by considering that she has a mu tation in one allele and that the other allele (or a mu tation in another locus) has a mutation that attenuates the synostosis of the vertebral bodies by interaction between alleles, or if it was in another locus an epistatic effect could have attenuated the phenotype16,17.

In KFS type II, with autosomal dominant inheri tance, variable expressivity has been described in cli nical severity18,19. Differences in synostosis in specific regions were observed in the cervical spine radiogra phs of the cases described. Since there was no apparent cause for the pathological gait of II-10 and II-14, it was presumed that it was related to KFS. These patients are highly predisposed to suffer spinal cord compression due to the transfer of mechanical forces through the malformed cervical spine20.

When interpreting family genealogy, it was defi ned that individuals (I-5, II-6, II-10, II-14, III-5) had symptoms compatible with KFS and with an autoso mal dominant inheritance pattern. Among the iden tified criteria for this type of inheritance is the phe notype that appears in all generations and one of the parents of each affected individuals is also affected. In an autosomal dominant inheritance pattern, affected individuals of both sexes have the same probability of transmitting the mutated allele and, consequently, also the phenotype to their children of both sexes; the in conspicuous expression of the disorder may give rise to apparent exceptions to this rule (Figure 4).

Considering the differences in time and morpho logy of vertebral bodies synostosis, differences in fre quency of fusion in specific regions, the most likely inheritance pattern is autosomal dominant and accor ding to the new KFS classification6, it is suggested that individuals in the studied family correspond to KFS type II associated with 8q22.1.

In the differential diagnosis approach (Table 1), chromosomal pathologies with a higher prevalence, such as Turner syndrome, should be considered among the first options, without forgetting monogenic disor ders. KFS has been described as a manifestation of fetal alcohol syndrome and a similar phenotype has been observed in maternal treatment with valproic acid21.

Table 1 Diagnostic difference of Klippel Feil Syndrome. 

Aphonia directly related to the malformation of laryngeal cartilages is present in 35% of individuals, Sprengel deformity characterized by scapulae in an unusually high position in 50% of them. Hearing mal formations occur most frequently in females with an M:F ratio of 1:1.5; neurosensory impairment is found in less than 30% of KFS cases, followed by mixed deaf ness and conductive deafness1.

In the skeletal system, scoliosis or kyphosis is present in 60%, in our cases corresponding to 40% in II-10, III-5 (Figure 1), while malformations of the urinary system with horseshoe kidney in 35%, and fa cial asymmetry and webbed neck with 20%. Among heart malformations, which are present in 4.2 -14%, severe lesions such as aortic coarctation may occur, however, ventricular septal defects are the most frequent15,22,23.

Mutations in the loci of the GDF3 gene (chro mosome 12p13.1), GDF6 (chromosome 8q22.1) and MEOX1 (chromosome 17q21.31) have been shown to be related to KFS24,25,26. In an investigation by Ye M et al., where multiple missense variants were identified in KFS families, it appears to represent one of the few studies reporting on the contribution of bone mor phogenetic proteins in heterozygous individuals with alterations in GDF3 and GDF6 genes10. The patients re ported in this research were not subjected to molecular studies, due to the absence of molecular sequencers in Ecuador.

Conclusions

The patient with congenital spinal deformity is a case of interest because it is an infrequent diagnosis in pediatric age and whose clinical suspicion can be gene rated from a good clinical examination and index case study, complemented with the interpretation of ge nealogy in Mendelian inheritance disorders, allowing timely genetic counseling.

The described clinical findings could give a pattern of high diagnostic suspicion, where the absence of the molecular study at the moment of establishing a diag nosis is no obstacle. Currently, molecular sequencers are not massively available, a fact that emphasizes the importance of the clinical evaluation described in this research.

Ethical Responsibilities

Human Beings and animals protection: Disclosure the authors state that the procedures were followed ac cording to the Declaration of Helsinki and the World Medical Association regarding human experimenta tion developed for the medical community.

Data confidentiality: The authors state that they have followed the protocols of their Center and Local regu lations on the publication of patient data.

Rights to privacy and informed consent: The authors have obtained the informed consent of the parents (tu tors) of the patients and/or subjects referred to in the article. This document is in the possession of the correspondence author.

Financial Disclosure: Authors state that no economic support has been asso ciated with the present study.

Conflicts of Interest: Authors declare no conflict of interest regarding the present study.

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Received: June 12, 2018; Accepted: January 02, 2019

Correspondence: Víctor Hugo Guapi Nauñay. E-mail: victor_hg7@hotmail.com.

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