Rhizomelic Dwarfism

Abstract

Rhizomelic dwarfism is a bone dysplasia that presents with a greater biometric reduction in rhizomelic structures, which are those more proximal to the trunk such as the humerus and femur. These dysplasias are developmental and become manifest in the third trimester or more often after birth. The diagnosis of dwarfism can only be made when the percentile of rhizomelic structures is equal to or less than third percentile. One must always rule out other causes of growth decalage such as gestosis or infection and, when ultrasound signs point to osteodysplasia, request a genetic examination.

The micromelic dysplasias with greater rhizomelic involvement are the object of study and knowledge of the researcher who every time he observes a dwarfism must ask himself many questions.

If, by performing an examination in the second trimester, we observe a symmetrically smaller fetus with all biometric parameters below the third centile, it could be a false “dwarfism.”

In this case, the observation of the crown rump length (CRL) performed in the first trimester will be decisive. If from this examination it is clear that the biometric delay already existed and was identical to the current one already in the first trimester, there is a mistake of gestational age, and the biometrics must be reshaped based on the presumed “time of conception.” If, on the contrary, an examination was not carried out in the first trimester, the pregnant woman must be informed that only by carrying out a biometric check after about 4 weeks will it be possible to differentiate the gestational mistake from other causes, including osteodysplasia.

In this case, an informative report should be carried out proposing, if in doubt, also the molecular genetic examination.

All the causes that can lead to reduced growth (infections, gestosis) are considered in the information.

It is obvious that this study methodology requires, however, for the sonographer, the knowledge of the signs associated with osteodysplasia.

1 Rhizomelic Dwarfism

Rhizomelic dwarfisms are bone dysplasias which, despite being micromelic, show a greater biometric reductive involvement in the rhizomelic structures (i.e., those proximal to the trunk: femur and humerus).

Almost all micromelic dysplasias are evolutive, an extremely important concept in ultrasound diagnostics because, except for the dysplasias that we have dealt with in the “lethal” chapter, which are very important biometric reductive development already at the end of the first trimester or at the beginning of the second trimester, all the others show “normal biometric growth” at 13–15 weeks to subsequently show a slow decalage becoming pathological, usually, in the third trimester.

In fact, to be classified as dwarfism, a centile equal to or lower than the third must be obtained, and this value, especially for rhizomelic forms, is reached only in the third trimester or, more often, after birth.

The sonographer, however, who observes a growth decalage that is not linked to any other problems, such as gestosis, must implement a precise path to exclude bone dysplasia.

It is also true that the wide variety of signs indicative of a possible osteodysplasia must lead to great caution with the need, in suspected cases, to request the study of the genetic panel of bone dysplasias.

The main rhizomelic dwarfisms are represented by:

• Achondroplasia

• Hypochondroplasia

• Chondrodysplasia punctata

• Metatropic dwarfism

• Diastrophic dwarfism

• Pseudo-diastrophic dwarfism

• Kyphomelic dysplasia

• Cranio-ectodermal dysplasia

• Omodysplasia

• Opsismodysplasia

2 Achondroplasia

Definition

Hereditary congenital disease, due to a growth disorder of the cartilaginous bone, which creates a disharmonic dwarfism with shortening of the bones of the limbs and the skull base, while the skeleton of the trunk is almost normal.

Incidence

It is the most common genotypic osteochondrodysplasia. Its incidence is 1/28,000 births.

Transmission

In 80% of cases, it is sporadic and the etiology is to be found in a de novo gene mutation. This mutation is transmitted as an autosomal dominant trait with a gene mapped in 4p16.3. The incidence of sporadic forms increases with increasing paternal age. The sex ratio is M1:F1.

Characteristic of the Anomaly

It is an osteochondrodysplasia of the growth plates with slowed endochondral ossification. This leads to a lack of development in length of the long bones, while the thickness is normal or even increased since periosteal ossification is not altered.

The early closure of the growth plates determines the micromelia and, also affecting the basilar plate of Kölliker, explains the abnormal brevity of the skull base. The saddle nose is related to the altered development of the ethmoid.

In the heterozygous form, the disease is characterized by mild rhizomelic dwarfism, curved limbs, lordosis, trident hand, prominent forehead with accentuated frontal bumps, and saddle nose.

In the homozygous form, micromelia is more severe and lethal (Figs. 1 and 2).

Fig. 1

The characteristic signs of achondroplasia

Fig. 2

Achondroplasia

Ultrasound Diagnosis

The homozygous form has some clinical and radiological aspects similar to thanatophoric dysplasia, the micromelia is severe, and it is easy for the operator to suspect it as both parents have achondroplasia.

In heterozygous form, there is a reduced biometry of rhizomelic segments that progressively decreases, usually after 24 weeks.

Often, in the third trimester, the biometric reduction is marked, remaining in any case of a mild type. Long bones reach values below the third centile and are flared and curved. Cranial biometry reaches very high centiles. The chest circumference is slightly reduced.

When the diagnosis is suspected, the prominent “boss” forehead and “saddle” nose can often be recognized. The most frequent associated anomaly is hydrocephalus.

In our experience, it was not possible to highlight the trident hand in uterus, except in a few cases, and always in the late third trimester. The “trident” hand is an almost constant postnatal sign.

The occurrence of polyhydramnios in the third trimester is possible [1, 2].

Ultrasound diagnosis is easy in the homozygous form, while ultrasound recognition is very difficult in the heterozygous form. It is possible to suspect this pathology only in the late third trimester.

In suspected cases or in the population at risk, genetic diagnosis on amniotic fluid is possible (Fig. 3).

Fig. 3

Achondroplasia in a fetus at 34 weeks: in (a), the prominent forehead known as “bossing” (FRONTE DA BOSS); in (b), lower limb with small biometry (tibia, femore); in (c), upper limb with small biometry (OMERO, DX, RADIO); in (d), isodactyly (MANO); in (e), the soft tissue redundancy (tess molli della coscia); in (f), nasal hypoplasia hypoplasia (naso piccolo); in (g), the regular biometry of the foot (piede); in (h), the “trident” hand (mano trident); in (i), the “sausage” fingers (dita salsicc); in (j), macrocrania

Other Considerations

After birth, limb-lengthening surgery (osteotomies) and correction of neurological compression complications (craniotomies, laminectomies) are possible.

Characteristic Signs

• Micromelic dwarfism with greater rhizomelic involvement

• Prominent forehead

• Small and saddle nose

• Soft tissue redundancy of the thigh

• Brachydactyly, isodactyly

• Trident hand (not frequent in uterus)

There is also a variety of achondroplasias associated with acanthosis nigricans in which there are hyperpigmented skin areas above all at the elbow and knee called the SADDAN form, which is however determined by the same mutated gene and whose diagnosis is only clinical and postnatal.

3 Hypochondroplasia

Definition

Osteodysplasia with micromelic dwarfism, similar to achondroplasia but without alterations of the facies and skull base and with more attenuated clinical and radiographic signs.

Incidence

About 1/100,000 births.

Transmission

It is determined by the same mutated gene as achondroplasia 4p16.3. It usually occurs de novo in parents who do not carry this mutation.

Characteristic of the Anomaly

It is similar to achondroplasia determined by the same mutated gene that is cataloged by geneticists as hypochondroplasia and which differs from achondroplasia because there are no facial signs (saddle nose, prominent “bossing” forehead) and also because the biometric slowdown is late and dwarfism becomes evident only in childhood.

Ultrasound Diagnosis

This osteodysplasia cannot be suspected with prenatal ultrasound alone, and the diagnosis is only molecular (Figs. 4 and 5).

Fig. 4

Hypochondroplasia: isodactyly and brachydactyly are observed

Fig. 5

Hypochondroplasia in a fetus at 25 weeks and 4 days. At the karyotype performed at 17 weeks, the mutated achondroplasia gene is highlighted: in (a), the femur is about 4 weeks smaller (sn); in (b), mild macrocrania; in (c), the nose is regular in biometrics; in (d), the prominent forehead and edema of the glabella (Profilo)

Characteristic Signs

• Slight and continuous biometric decalage that almost never reaches the third centile

• Brachydactyly

• Normal-sized nose

• Soft tissue exuberance of the limbs

4 Chondrodysplasia Punctata

Definition

Congenital disease, with polymorphic clinical manifestation affecting various tissues of meso-ectodermal derivation, characterized by the presence of epiphyseal calcifications and dysplastic bone alterations, frequently associated with severe general disability, micromelia, and various dystrophies (ocular, cutaneous, cardiac, and skeletal).

Incidence

About 1/140,000 births.

Transmission

At least nine different types with different mutated genes and heterogeneous inheritance: autosomal dominant, recessive, and X-linked are classified as chondrodysplasia punctata. The main mutated genes are Xp11.23, 6p22.24, 1q42, 2q31, Xq28, Xp11, and Xp22.3.

Characteristic of the Anomaly

The common sign is the rhizomelic micromelia and the presence of microcalcifications that can affect several bones with a variable percentage as can be seen in the table (Fig. 6).

Fig. 6

Site of microcalcifications in dysplasia punctata

From this table, it is observed that only in 3% of cases extracartilaginous tissues are involved (for example, cataracts) and only in these cases the association with mild rhizomelic dysplasia can vaguely suspect, through the ultrasound investigation, this disease which will be recognized only by genetic investigation. In fact, the main sign of the presence of epiphyseal microcalcifications is not found in the prenatal period, but only radiologically after birth.

Punctata dysplasia therefore manifests itself with a polymorphic clinical picture since it affects tissues of mesoectodermal derivation. There are mainly epiphyseal calcifications and bone alterations of the chondrodystrophic type associated with micromelia. Skin, ocular, cardiac, and skeletal changes are possible. In the rhizomelic form, the only one that can be recognized in the prenatal period, there is reduced biometry of the proximal segments of the limbs.

There are facial anomalies with a flat profile, prominent forehead, and saddle nose. Hypertelorism may be present. The non-rhizomelic type has a slight, or sometimes absent, involvement of the bone segments. Contractures may be present, and ascites and polyhydramnios are reported.

Antenatal diagnosis is sometimes suspected in rhizomelic forms.

The Conradi-type form has a low mortality with normalization of the clinical picture in 2–3 years. The dominant X-linked type is lethal in the male; the recessive form has an intermediate severity (Figs. 7 and 8) [3].

Fig. 7

Chondrodysplasia punctata (rhizomelic form)

Fig. 8

Two cases of congenital cataract present in my archive observed in the second trimester are represented in (a, b) (occhio sn, CATAR, CRISTALLIN). The observation of this anomaly is an indication for the molecular genetic study

Ultrasound Diagnosis

The sign that can induce the sonographer to request the genetic examination is the progressive biometric reduction especially of the humerus and the femur, which most often is accentuated only in the third trimester. The presence of congenital cataract or myocardial microcalcifications can generate a vague suspicion. In some cases, the relief of a flat profile and a “saddle” nose can increase diagnostic accuracy. The diagnosis is however molecular.

Other Considerations

In cases at risk of recurrence, the diagnosis is made with the chorionic villus sampling looking for the mutated gene.

Characteristic Signs

• Progressive biometric decalage of the biometry of long bones mostly at the rhizomelic level

• Cataract

• Myocardial microcalcifications

• Flat profile

• Saddle nose

5 Metatropic Dysplasia

Definition

Congenital disease with changing clinical picture, characterized in the “initial phase” by an achondroplastic micromelia and in the “late” phase by a severe kyphoscoliosis with shortening of the trunk, evoking Morquio disease. Metatropic dwarfism owes its name to the mutability of the clinical picture (in Greek language, metatropic means variable).

Incidence

About <1/1,000,000 births.

Transmission

It is transmitted within a heterogeneous way as cases with autosomal recessive or dominant inheritance and sporadic cases with mutated gene sometimes in 12q24.11.

Characteristic of the Anomaly

There is a severe spondylo-epi-metaphyseal dysplasia. Progressive kyphoscoliosis results in an inversion of proportions in childhood, with shortening of the trunk and relatively long extremities. The face of the newborn is slightly dysmorphic, while it can be normal in the following years.

It is characterized in the initial phase by achondroplastic micromelia and after birth kyphoscoliosis with shortening of the trunk occurring in a worsening manner.

It is a dysplasia characterized by abnormal morphology of the metaphyses of the long bones that appear 2–3 times larger than the diaphyses; this determines a “club” aspect; the chest is tight; occasionally, a taillike coccygeal appendage is present [4].

Ultrasound Diagnosis

A rhizomelic dysplasia with widened diaphysis and a bell-shaped thorax characterized by low centiles with advancing age (e.g., 20th centile) and with the possible presence of scoliosis (rarely before the third trimester) can be observed. These signs allow us to suspect the malformation, which however is evolutive in an extremely pejorative prognosis for the trunk and spine; it will be assessed for its severity months after birth. Obviously, only the presence of the mutated gene, upon invasive investigation, allows prenatal recognition (Fig. 9).

Fig. 9

Image taken from the archive showing a rhizomelic dysplasia in a fetus at 15 weeks. The observation of a rhizomelic micromelia, especially when there is an enlarged diaphysis, should lead to the genetic study of the bone dysplasia panel (omero)

Another Consideration

Being almost always sporadic, the recurrence in the family is difficult even if there are rare cases of involvement in the brothers.

Characteristic Signs

• Rhizomelic micromelia

• Diaphysis enlarged in the proximal part

• Short trunk

• Scoliosis.

6 Diastrophic Dwarfism

Definition

Congenital disorder characterized by stature retardation, micromelia, clubfoot, postnatal scoliosis, joint stiffness, and ear pinna abnormalities.

Incidence

1/3000 births.

Transmission

It is transmitted with autosomal recessive and variable expressiveness with mutated gene in 5q31–34.

Characteristic of the Anomaly

It is characterized by short stature with short extremities (adult stature is 120 cm ± 10 cm) and joint stiffness, secondary to multiple joint contractures (especially of the shoulders, elbows, and interphalangeal and hip joints). This condition affects both males and females.

It is a heterogeneous bone dysplasia characterized by micromelia, club foot, deformities of the hands, defects of the auricles, multiple joint contractures in flexion, and scoliosis.

A characteristic sign is the “hitchhiker thumb.” Auricular cysts representing a characteristic sign (cauliflower ear) usually appear after birth.

In relation to the variable expressiveness, there are lethal forms and other forms with good prognosis and normal intelligence (Figs. 10, 11 and 12) [5].

Fig. 10

Diastrophic dwarfism

Fig. 11

Diastrophic dwarfism: ear cyst from “ear to cauliflower.”

Fig. 12

Newborn affected by diastrophic dwarfism

Ultrasound Diagnosis

Micromelia is observed with the main involvement of the humerus and the femur; clubfoot coexists. Scoliosis may already be visible in the second trimester although it usually occurs in the third trimester. In addition to short limbs, multiple contractures are characteristic signs.

The micromelia is moderate and therefore not reaching a low percentile in uterus (below the third centile) is not a typical sign. On the contrary, the suspicion derives from the observation of “joint stiffness”; the hands are deviated in an ulnar side. The thumb is implanted more proximally than normal with a “hitchhiker” appearance.

This sign is very indicative of the disease; there are deformities, usually in flexion, of the elbow and knee joints; scoliosis and micrognathia may be present.

The other associated anomalies are eye anomalies, facial hemangioma, craniosynostosis, and heart septal defects. The laryngeal tracheal stenosis is possible, and the suspect is possible because there is the presence of a “hyperechoic” part of the lung.

Other Considerations

The diagnosis can be suspected in the second trimester in severe forms and confirmed by genetic investigation.

Genetic diagnosis is used in fetuses at risk.

In the severe form, growth retardation and heart disease are often associated (Figs. 13, 14 and 15).

Fig. 13

Images taken from archive in a fetus at 17 weeks: in (a), “hitchhiker’s thumb” (mano dx); in (b), triphalangeal thumb with minuscule accessory phalanx (3, police)

Fig. 14

Image from archive showing joint stiffness and bilateral clubfoot. Molecular karyotype should always be recommended, and diastrophic dwarfism is among the various syndromes (PIEDE TORTO)

Fig. 15

Diastrophic dwarfism: in (a), the hitchhiker’s thumb (MANO DX, POLLICE); in (b), the fetus at birth: macrocrania, globose abdomen, joint stiffness, hitchhiker’s thumb; in (c, d), the radiological survey showing “bell-shaped” chest, globose abdomen, short and stubby diaphysis with wide metaphysis, and clubfoot

Characteristic Signs

• Rhizomelic micromelia

• Joint stiffness (especially clubfoot)

• “Hitchhiker” thumb

• Scoliosis

• Ear anomalies

7 Pseudodiastrophic Dysplasia

Definition

Osteodysplasia present at birth, characterized by micromelia, platyspondylia, congenital scoliosis, and clubfoot with often fatal evolution.

Incidence

<1/1,000,000 births.

Transmission

The very few cases described indicate an autosomal recessive transmission, but the mutated gene was not recognized.

Characteristic of the Anomaly

It is similar to diastrophic dwarfism and differs from it for different radiological aspects especially in the chest where a relief of shorter ribs is observed compared to diastrophic dwarfism, and this explains the higher perinatal mortality (Figs. 16 and 17) [6].

Fig. 16

Pseudodiastrophic dwarfism

Fig. 17

Pseudodiastrophic dwarfism

Ultrasound Diagnosis

Rhizomelic dwarfism, clubfoot, joint stiffness, scoliosis, and narrow chest are observed (Fig. 18).

Fig. 18

Images from the archive of a fetus with suspected diastrophic dwarfism with narrow chest (a) (torace, addome) and hitchhiker’s thumb in (b) (Mano)

Other Considerations

Since the mutated gene is not known, the use of molecular investigation does not help in the diagnosis, which will be implemented only after birth with the radiological investigation.

Characteristic Signs

• Rhizomelic dwarfism

• Joint stiffness

• “Hitchhiker” thumb

• Extremely narrow chest

• Scoliosis

8 Kyphomelic Dysplasia

Definition

Dysplasia of the skeleton already present at birth, characterized by abnormal shortness of the limbs associated with diaphyseal curvature.

Incidence

<1/1,000,000 births.

Transmission

It is transmitted in an autosomal recessive manner, but, to date, the mutated gene has not been recognized.

Characteristic of the Anomaly

It is radiologically characterized by short and squat long bones, strongly curved femurs, short and wide iliac wings with horizontal acetabular roof, platyspondylia, and narrow thorax, manifesting clinically with a statural delay. The curvature of the femoral angulation lessens with advancing age (Fig. 19) [7].

Fig. 19

Kyphomelic dysplasia

Ultrasound Diagnosis

Curved limbs are observed, especially the femur, characterized by mild rhizomelic biometric retardation. The important differential diagnosis is with campomelic dysplasia, of which the mutated gene is known.

Obviously, if the phenotype is male, the hypothesis of kyphomelic dysplasia is more credited than the campomelic one, since in the latter the phenotype is very often female (Figs. 20 and 21).

Fig. 20

Suspected kyphomelic dysplasia in a fetus at 21 weeks: in (a), curved femur (femore SN); in (b), curved tibia and fibula (Gamba sn, tibia, fibula); in (c), the foot is straight and there is soft tissue exuberance (piede sn); in (d), humerus, hypoplastic, has a “club” appearance (omero sn)

Fig. 21

: Suspected kyphomelic dysplasia in a fetus at 13 weeks: in (a), the curved femur; in (b), the humerus has a slight curvature in the distal portion (Omero); in (c), the axis of the foot is straight (PIEDE DRITTO); in (d), the genitals are male (DOVREBBE ESSERE XY); in (e), the tibia and fibula are curved (TIBIA E FIBULA); in (f), the ulna and the radius are curved (ULNA E RADIO)

Characteristic Signs

• Curved long bones with greater involvement of the femur

• Rhizomelic micromelia

• Clavicular hypoplasia

• Bell-shaped chest

9 Cranioectodermal Dysplasia

Definition

Familial syndrome characterized by dolichocephaly and hair and tooth anomalies associated with short limbs.

Incidence

<1/1,000,000 births.

Transmission

It is an autosomal recessive disorder with multiple genes involved: 3q21.3q22.1, 14q24.3, 20q13 12, 4p14, and 2p2.41.

Characteristic of the Anomaly

Craniosynostosis/dolichocephaly, narrow chest, rhizomelic micromelia, brachydactyly, syndactyly, clinodactyly, and joint hyperextensibility are present; it is associated with ectodermal defects, such as anomalies of the teeth (reduced thickness of the enamel, hypodontia, microdontia, taurodontism, malformations of the cusps), sparse hair, and anomalies of the fingers and toes. Some dysmorphisms have also been observed, such as epicanthus, hypotelorism, anteverted nostrils, and prominence of the upper lip. Patients often develop chronic renal failure from nephronophthisis, usually between the ages of 2 and 6 years. The liver may be involved (hepatic fibrosis) [8].

Ultrasound Diagnosis

The suspicion arises from the finding of a rhizomelic dysplasia associated with dolichocephaly due to the prevalence of the fronto-occipital diameter over the biparietal diameter. Only molecular diagnosis allows prenatal recognition (Fig. 22).

Fig. 22

Suspected cranio-ectodermal dysplasia in a fetus at 17 weeks and 2 days: in (a), dolichocephaly with head circumference corresponding to 16 weeks and 0 day (TESTA); in (b, c), the long bones of the lower limbs correspond to about 14 weeks and 4 days (FEMORE, TIBIA); in (d, e), the same biometric delay in the long bones of the upper limb (OMERO, RADIO); in (f), brachydactyly with clinodactyly of the fifth finger (MANO)

Characteristic Signs

• Craniosynostosis

• Dolichocephaly

• Rhizomelic micromelia

• Brachydactyly

• Syndactyly

10 Omodysplasia

Definition

Malformation syndrome characterized by peculiar facies and abnormal shortness of the humerus and sometimes also of the femur.

Incidence

<1/1,000,000 births.

Transmission

It is transmitted with genetic heterogeneity (dominant with mutated gene in 17q21.3 1; recessive with mutated gene in 13q31.3-q32.1).

Characteristic of the Anomaly

Peculiar facies with prominent forehead and hypoplastic and saddle nose are observed; rhizomelic micromelia with greater involvement of the humerus on the femur; in the male, hypogenitalism with micropenis is seen (Figs. 23 and 24) [9].

Fig. 23

Omodysplasia

Fig. 24

Image taken from the archive showing hypogenitalism with micropenis (IPOGENITALISMO)

Ultrasound Diagnosis

The sign of suspicion is given by rhizomelic dwarfism, which leads to molecular diagnosis.

Characteristic Signs

• Humeral rhizomelic micromelia

• Prominent forehead

• Saddle nose

• In the male, hypogenitalism

11 Opsismodysplasia

Definition

Syndrome characterized by peculiar facies, rhizo-acromelic micromelia, and marked delay in ossification.

Incidence

<1/1,000,000 births.

Transmission

The inheritance is autosomal dominant with the mutated gene in 11q13.4.

Characteristic of the Anomaly

Rhizomelic micromelia, macrocrania, small and saddle nose short neck, narrow chest, scoliosis, and hypotonia are observed (Fig. 25) [10].

Fig. 25

Opsismodysplasia: short, stubby hands in a baby at 14 months; severe ossification retardation

Ultrasound Diagnosis

The suspicion arises from the association of rhizomelic dwarfism and hypotonia.

Obviously, the diagnosis is delegated to genetics.

Characteristic Signs

• Rhizomelic micromelia

• Macrocrania

• Nasal hypoplasia

• Saddle nose

• Short neck

• Tight chest

• Fetal hypokinesia

12 Conclusions

Rhizomelic dysplasias are rare, although achondroplasia is the most common dwarfism.

The sonographer must know that when he sees a biometric reduction of the limbs with a prevalence of the rhizomelic tract, he must perform a careful study of all the systems with a precise description of the cranial morphology because, usually, macrocrania prevails but sometimes the morphology is regular and, at other times, there is dolichocephaly (for example, in cranio-ectodermal dysplasia); describe if there is prominent forehead (for example, in achondroplasia) and see the nose and thoracic morphology; observe if there is scoliosis; describe if there is joint stiffness, and obviously perform careful observation of all the other systems (lens, heart, kidney, etc.).

Genetic counseling and the study of the molecular karyotype must always be requested.

The pregnant woman, since the diagnosis is made most often in the third trimester, will evaluate whether to carry out the molecular diagnosis during gestation or after birth.