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2004-08-25-14 Kniest syndrome © Cuillier www.thefetus.net/


Kniest syndrome

Dr Cuillier F. MD, Dr Cartault F. MD, Dr.Chaitali Shah, MD (*) Dr Lemaire P., Dr Alessandri J.L.

Department of Gynecology, Hôpital Félix Guyon, 97400 Saint-Denis, La Réunion. France.
Tél : 0262 90 55 40. Fax : 0262 90 77 30. Email : fabrice.cuillier@wanadoo.fr
Department of Genetic, Hôpital Félix Guyon, 97400 Saint-Denis, La Réunion. France.
Echography’office, 10 Route de Moufia, 97490 Sainte-Clotilde. La Réunion. France.
Department of Neonatology, Hôpital Félix Guyon, 97400 Saint-Denis, La Réunion. France. (*) www.thefetus.net/

Synonyms: Metatropic Dwarfism type II; Metatropic Dysplasia type II; Pseudo-metatropic Dwarfism; Kniest syndrome, Swiss cheese cartilage syndrome, Kniest chondrodystrophy.

Definition: Kniest dysplasia is a short trunk chondrodysplasia caused by defective formation of type II collagen1. It is a subtype of type II and XI collagenopathy. This skeletal dysplasia incorporates disproportional dwarfism, unusually short arms and legs and is compatible with life and normal intelligence. Patients however may have vision and hearing problems; and may excrete keratan sulphate in their urine.

Kniest syndrome is characterized by the involvement of the: 2,4

  • Spine (platyspondyly and coronal or vertical clefting of the vertebral bodies with eventual kyphoscoliosis and lumbar lordosis),
  • Pelvis (small iliac bones with increased acetabular angles; inadequate ossification of pubic rami).
  • Tubular bones (short and bent bones, metaphyseal flaring, contracture of fingers and premature  osteoarthritis) 
  • Thorax (short thorax, may be broad or narrow).
  • Craniofacial abnormalities [may be present; and include a deep posterior fossa, tracheomalacia, occipitoatlantal instability, midface hypoplasia and cleft palate].
  • Eyes [proptosis, myopia, glaucoma, vitreoretinal degeneration, retinal detachment, dislocated lenses]
  • Ears [chronic otitis media, deafness]. 
  • Inguinal hernia may be present.

Case report: 
To our knowledge, our case is the third of Kniest dysplasia diagnosed before the pregnancy was terminated 3,5,19. In the case presented here, prenatal diagnosis by ultrasound led to differential diagnosis of a severe but non lethal skeletal dysplasia. Kniest dysplasia was the most probable diagnosis considering the ultrasound findings such as markedly shortened but unbent bones, the normal head circumference, lack of thoracic dysplasia and the family history.

Ultrasound scan performed in a 25-year-old mother. They had an elder son who was short statured. These are the scans obtained at 23 weeks of gestation.

Routine ultrasound revealed short limbs of the fetus without polyhydramnios. All the long bones were less than the fifth percentile but were normally shaped. The hands and feet were disproportionately long. There was no ulnar deviation of hands and no polydactyly. Ossification appeared normal and no fractures were evident. Normal range of movements was observed. The chest was of normal appearance but the thorax was relatively short and slightly narrow (the thoracic circumference seems just beneath the normal range). The head circumference and biparietal diameter were normal and no frontal bossing was discernible. No other anomaly was found on ultrasound in this female fetus, except the appearance of exophthalmia . Malformations of other organ systems were excluded. The placenta, the umbilical cord and the amount of amniotic fluid were normal.

 

The baby was delivered in good condition by a caesarean section.(P = 2.8 Kg and Apgar scores were 9 at 1 min and 10 at 5 min). Her occipito-frontal circumference was on the fifth percentile and her length [45cm] was below the third percentile. The baby was noted to have a mildly dysmorphic face.The limbs were short with normal hands and feet. There was normal flexion of the fingers and toes and normal range of movements in the joints. Systemic examination showed no other abnormalities and no hepatosplenomegaly. Routine cardiological assessment showed normal structure. X-rays of the long bones showed symmetrical short tubular bones with normal metaphyses, no dislocation of the digits and no other dysplastic features. There was no malformation of the spine or platyspondylia. At six weeks of life, the weight of the baby is 3.8 kg and length is 49 cm.

 

The postnatal appearance of the neonate with Kniest syndrome denotes the peculiar rounded face that is depressed in the midpart, hypertelorism, antimongoloid position of the eyes, large low set ears and small mouth. The characteristic short long bones and the normal toes are also seen. 

 

 

 

History: Skeletal dysplasias vary in their natural histories, the mode of occurence, etiopathogenetic mechanisms and their prognosis.

The first case of Kniest dysplasia was described by Dr. Wilhelm Kniest in 1952 in a male patient, while he was the chief resident of the Children"s Hospital of the University of Jena in Thuringia. Spranger, et al in 1997 studied this original patient, who at that time was 50 years old, was severely handicapped with short stature, had restricted joint mobility and was blind. He was however mentally alert and lead an active life. A molecular analysis of this original patient"s DNA showed a single base (G) deletion involving the GT dinucleotide at the start of intron 18 destroying a splice site of the COL2A1 gene. This was in accordance with the molecular findings in other patients with Kniest dysplasia 16

There are various citations in literature regarding the different features seen in Kniest syndrome. Some of these are –

1. Siggers et al. reported Kniest syndrome in 1974 in eight patients, of which two were identical twins and the other cases were sporadic. Cleft palate was present in 5, deafness in 6 and retinal detachment in 3.
2. Kim et al. in 1975 described a pair of affected mother and daughter. The daughter had myopia and chorio-retinal thinning; the mother had cataracts and myopia. They had excessive urinary excretion of keratan sulfate.
3. Stanescu et al. in 1976 suggested that an abnormal proteoglycan is synthesized in this disease.
4. Horton and Rimoin in 1979, described chondrocyte inclusions.
5. Friede et al. in 1985 confirmed the high urinary excretion of keratan sulfate in patients with Kniest dysplasia. They described characteristic morphological cranio-facial changes that included macrocephaly, a short and wide odontoid process and retropositioned facial skeleton.
6. Maumenee and Traboulsi in 1985 described ocular findings in 7 patients with Kniest dysplasia. All of them had severe congenital myopia and vitreo-retinal degeneration. Rhegmatogenous retinal detachment developed in 4 of them, cataract in two, dislocated lenses in one, and blepharoptosis in one.
7. Poole et al. in 1988 and Gilbert-Barnes et al. in 1996 demonstrated abnormality of collagen fibril organization in patients with Kniest dysplasia 17. Fibrils were much thinner than normal and were irregular in shape, without the characteristic banding pattern. Furthermore, chondrocalcin was found to be absent from the extracellular matrix of epiphyseal cartilages and to be abnormally concentrated in intracellular vacuolar sites where it was not part of the procollagen molecule. Type II collagen alpha chain size was normal, indicating the formation of a triple helix; the content of type II collagen was also normal. Poole et al. concluded that the defect in Kniest dysplasia results from the secretion of type II procollagen lacking the C-propeptide [which is required for normal fibril formation] and therefore, resulting in abnormal fibril formation.

All these cases were diagnosed in childhood and it is only recently that antenatal diagnosis is being made.

Prevalence: The exact incidence of Kniest is not known, however it is very uncommon.
Etiology: Most of the cases have been sporadic [including the original case reported by Kniest]; but many authors have suggested a familial trait, with an autosomal dominant inheritance.
Kniest dysplasia phenotype results from mutations in the gene for type II collagen, COL2A1. The other clinical conditions caused by mutations in the COL2A1 gene coding for type II collagen other than Kniest include achondrogenesis II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita, Stickler arthro-ophthalmopathy and mild dominant spondyloarthropathy. These mutations are expressed in the heterozygous states.

The mutations occurring in Kniest dysplasia phenotype are random and are in frame deletions in type II collagen. These may be either small deletions in the gene or splice site alterations. All of these alterations are usually located between exons 12 and 24 in the COL2A1 gene. Wilkin, et al in one of his study, concluded that point mutations which result in single amino acid substitutions [glycine103 of the triple helical domain by aspartate] could produce Kniest dysplasia.

Pathology: Secretion of a type II procollagen lacking in C-propeptide [C-propeptide is essential for normal fibril formation], results in abnormal fibril assembly and is responsible for the characteristic chondro-osseous histopathological picture. Lacunae in the cartilage make it soft and crumbly and this has been likened to the appearance of ‘swiss-cheese’, and hence the name ‘Swiss cheese cartilage syndrome’. A disorganized physeal growth plate and diastase resistant intracytoplasmic inclusions in the enlarged resting chondrocytes have been reported. Transmission electron microscopy would show dilated cisternae of rough endoplasmic reticulum with finely granular material of accumulated protein.

Implications for targeted examinationsDwarfism is a commonly used term for disproportionately short stature, although a more medically appropriate term is skeletal dysplasia (for the parents, it is less traumatic). Short stature is defined as a height that is three or more standard deviations below the mean height for age. If the short stature is proportional, the condition may be due to an endocrine disorder, a metabolic disorder, a chromosomal or non skeletal dysplasia genetic defect.

In general, patients with a disproportionately short stature have a skeletal dysplasia (osteochondrodysplasia) that is characterized by abnormalities of cartilage and bone growth. The diagnosis can be difficult; however in this case, one clue was the history of an affected sibling.

Sonographic findings:
With the advents in two and three-dimensional (2D and 3-D) imaging, the detection of prenatal-onset skeletal dysplasias has improved tremendously. However, generating a precise diagnosis can be challenging and there are many underlying reasons for this. Many of the clinical and radiological findings that delineate these skeletal dysplasias are not well visualized by 2D imaging, and therefore an accurate diagnosis may be difficult to achieve.

At the time of the publication of the book by Romero, Jeanty, et al [1987], the prenatal diagnosis of Kniest dysplasia had not yet been reported. The antenatal diagnosis of Kniest dysplasia is extremely rare; only three cases have been described so far in the literature. Bromley et al in 1991 described the first antenatal discovery of Kniest dysplasia and the second one was described by Kerleroux. The third antenatal diagnosis of Kniest dysplasia is described in this report.

The following sonographic abnormalities might be seen:

  1. Extremities – disproportionate dwarfism, shortening of the limbs, [in the case described here, the hands and feet were disproportionately long as compared to the long bones], flaring of the metaphyses and delayed appearance of the ossification centers in the femoral head.
  2. Spine – may demonstrate platyspondyly, coronal clefting of the vertebral bodies.
  3. Thorax – may be short and narrow; however, it is not severe enough to cause pulmonary hypoplasia.
  4. Craniofacial region – cleft palate, flat nasal bridge, hypertelorism, flat facies.
  5. Polyhydramnios. 
  6. Fetal movements – usually normal. The lethal form of Kniest [discussed later] may have reduced fetal movements.

Kniest like- Dysplasias-

  1. Sconyer’s type- lethal form of Kniest, is autosomal recessive, the differentiating features are severe growth plate and cartilage changes, markedly shortened bones and metaphyseal changes.
  2. Burton syndrome - clinical and radiological features resemble Kniest, but patients with Burton’s syndrome have microstomia, pursed lips and ectopia lentis [whistling face]; these patients also do not show characteristic swiss-cheese appearance of the bones seen in Kniest.
  3. Hunter, et al variant – milder than Kniest, autosomal recessive, primarily hand and spine involvement.
  4. Currarino type- the vertebrae have more severe coronal clefts and milder long bone involvement.
  5. Farag, et al variant- autosomal recessive, more lethal, persistently anterior wedged vertebrae.

Differential diagnosis:
Although the prenatal recognition of chondrodysplasia is increasingly accomplished in cases without a family history, it is often difficult to make a precise diagnosis. Most skeletal dysplasias, which have a prior low genetic risk and which are diagnosed during pregnancy, are usually lethal in the new-born. Thanatophoric dysplasia, Osteogenesis imperfecta [certain types] and Camptomelic dysplasia are the most frequently occurring lethal disorders and are commonly associated with polyhydramnios. These as well as Achondroplasia and Achondrogenesis are easily eliminated from the differential diagnosis. Kniest syndrome should be considered as a part of the differential diagnosis of skeletal dysplasias associated with metaphyseal flaring (metatropic dysplasia, fibrochondrogenesis and Weissenbacher-Zweymuller). The important syndromes that need to be considered in the differential diagnosis include:

  1. All the Kniest-like dysplasia syndromes.
  2. The less severe form of Dyssegmental dysplasia [called as Rolland-Desbuquois syndrome] - radiological appearance is similar to Kniest;
  3.  Metatropic dysplasia type I –in this, the thorax is long and narrow and the long bones are dumbbell shaped. Moreover, fetuses with metatropic dysplasia do not have facial features similar to those seen in Kniest.
  4. Spondyloepiphyseal dysplasia congenita –the body configuration and the radiological changes are similar to Kniest, ? except for the dumbbell shaped limb bones, 
  5. Morquio’s disease- this disease usually becomes detectable between 1-3 years of age.
  6. Weissenbacher-Zweymuller dysplasia- consists of micromelia with dumbbell configuration of long bones, micrognathia and coronal clefting of the vertebrae (there is no platyspondyly as seen in Kniest dysplasia).

Prognosis:
This disorder is compatible with life. However there is development of progressive disability due to kyphoscoliosis. Concomitant deafness and ocular involvement are also major incapacitating complications. Therefore, periodic surveillance must be carried out for these patients.

Recurrence risk:
Kniest dysplasia is an autosomal dominant chondrodysplasia, although sporadic sometimes. Accurate genetic counseling of the parents requires a definitive diagnosis. Since many mutations for this dysplasia are known, genetic mapping may be able to provide an accurate diagnosis.

Management:
In cases of prenatal diagnosis of fetal dwarfism, the problem is to make an accurate diagnosis of the disease using careful ultrasonographic and radiological examination. But in many instances, only a differential diagnosis can be given prenatally and prognosis is often limited to the distinction between a lethal or non-lethal type of dysplasia. Once a non lethal type of dysplasia has been diagnosed, the degree of growth impairment needs to be assessed.
Romero and Jeanty, et al in thier book quoted that the antenatal detection of Kniest syndrome after viability, would not alter the standard obstetrical management.Since Kniest syndrome is a non-lethal skeletal dysplasia with patient having a normal life span and intelligence, the management postnatally involves periodic monitoring with an aim to prevent the occurrence of complication sif possible, and recognize and treat them, when present.


References:
1. Wilkin DJ, Bogaert R, Lachman RS, et al. A single amino acid substitution (G103D) in the type II collagen triple helix produces Kniest dysplasia. Hum Mol Genet. 1994 Nov;3(11):1999-2003.
2. Maroteaux P, spranger J. La maladie de Kniest. Arch Fr Pediatr 1973; 30: 735-50.
3. Lo IF, Roebuck DJ, Lam ST, Kozlowski K. Burton skeletal dysplasia: the second case report. Am J Med Genet. 1998 Sep 23;79(3):168-71.
4. Spranger J, Winterpacht A, Zabel B. The type II collagenopathies: a spectrum of chondrodysplasias. Eur J Pediatr. 1994 Feb;153(2):56-65.
5. Burton BK, Sumner T, Langer LO Jr, Rimoin DL, Adomian GE, Lachman RS, Nicastro JF, Kelly DL, Weaver RG. A new skeletal dysplasia: clinical, radiologic, and pathologic findings. J Pediatr. 1986 Oct;109(4):642-8.
6. Sconyers SM, Rimoin DL, Lachman RS, Adomian GE, Crandall BF. A distinct chondrodysplasia resembling Kniest dysplasia: clinical, roentgenographic, histologic, and ultrastructural findings. J Pediatr. 1983 Dec; 103(6):898-904.
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9. Currarino G. unusual bone dysplasia featuring severe platyspondyly and vertebral coronal cleft in infancy and changes of metaphyseal chondrodysplasia in childhood. Peadiat Radiology. 16:43-36. 1986.
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11. Hunter, et al. An unusual skeletal dysplasia with platyspondyly and marked digital involvement: a new entity? Prog. Clin.Bio.res. 104:111-18. 1982.
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