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Tricho-Rhino-Phalangeal syndrome is a rare autosomal dominant genetic disorder caused by mutations in the TRPS1 gene. This malformation syndrome is characterized by distinctive craniofacial features including sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. In this report, we describe two patients with the physical manifestations and genotype of TRPS type I but with learning/intellectual disability not typically described as part of the syndrome. The first patient has a novel heterozygous two-base-pair deletion of nucleotides at 3198-3199 (c.3198-3199delAT) in the TRPS1 gene causing a translational frameshift and subsequent alternate stop codon. The second patient has a 3.08 million base-pair interstitial deletion at 8q23.3 (113,735,487-116,818,578), which includes the TRPS1 gene and CSMD3. Our patients have characteristic craniofacial features, Legg-Perthes syndrome, various skeletal abnormalities including cone shaped epiphyses, anxiety (first patient), and intellectual disability, presenting unusual phenotypes that add to the clinical spectrum of the disease.

Highlights • EVC syndrome is very rare in the Middle East. • We report on a Saudi family with two affected children. • Gene analysis revealed a homozygous c.2T >A in exon 1 of the EVC gene. • The most interesting finding was the wide-spread cone-shaped epiphyses., Introduction Ellis-van Creveld (EVC) syndrome is one of the rarest ciliopathy syndromes. It is caused by mutations of the EVC and EVC2 genes which encode the EVC proteins present in the basal body of the primary cilium. Presentation of cases We report on a Saudi family with two affected children. Gene analysis revealed a homozygous c.2T >A in exon 1 of the EVC gene. The most interesting finding in our patients was the wide – spread cone-shaped epiphyses in the hands and feet. Discussion Although cone-shaped epiphyses is a known feature of EVC syndrome, it usually limited to the middle or proximal phalanges. The wide-spread cone-shaped epiphyses seen in our patients have not been previously reported. Conclusion EVC syndrome is very rare in the Middle East. We report on the first Saudi family with EVC syndrome confirmed by gene analysis. The most unique finding in our patients was the wide-spread cone-shaped epiphyses in the hands and feet. The abnormality is probably related to abnormal Indian hedgehog signaling in the primary cilium.

Acrodysostosis is characterized by distinctive facial features and severe brachydactyly. Mutations in PRKAR1A or PDE4D are known to be responsible for this disease. Cases of hormonal resistance have been reported, particularly in patients with PRKAR1A mutations. The physical characteristics and endocrine function of pseudohypoparathyroidism type Ia is known to resemble acrodysostosis. We report the case of a 4-yr-old patient with a PRKAR1A mutation. He had characteristic facies with an upturned nose and cone-shaped epiphyses of most phalanges. These findings have not been reported as extensive for cases of pseudohypoparathyroidism type Ia. He also had TSH resistance from birth. We performed endocrinological stimulation tests to further evaluate his endocrine status. These examinations revealed resistance to TSH and PTH, but there was normal secretion of ACTH, GH, and cortisol. An Ellsworth-Howard test resulted in normal urinary cAMP excretion. This response differs from that of pseudohypoparathyroidism type Ia. In summary, the constellation of an upturned nose, cone-shaped epiphyses of most if not all phalanges, and PTH resistance with a normal urinary cAMP response may satisfactorily enable clinical diagnosis of acrodysostosis.

Systemic disorders of the skeleton have either a primary or endogenous, mostly heritable cause like osteochondrodysplasias or they are secondarily or exogenously caused by pathologic influence of the metabolic or endocrine system. The functional unit of growth plate and epiphysis is frequently the target organ of these pathologic influences. The pathogenetic effect on the skeleton is manifested as a disturbance of growth and as an epiphyseal deformity and structural change. Here one must take in consideration the fact that these pathological influences affect not only the epi-and apophyses of tubular bones but also those of the skull, the pelvis and the spine. Because of that and because of the unequal quantitative effect of growth at different growth plates and the chronological different developmental state of the epiphyses, very variable disorders are the result. Disturbances of growth lead to proportional or disproportional short or tall stature. Epiphyseal deformations may have the consequence of contractures and early osteoarthritis. Joint replacement at the hips and knees is inescapable and requires, because of the diminutive skeletal proportions, a special custom -made prosthetic device. Slight epiphyseal deformities, like cone shaped epiphyses, result not so much in functional disturbance but may rather be used as a diagnostic clue. By means of the most typical and important systemic skeletal disorders the pathogenetic principles are discussed.

Brachydactyly is a common feature of pseudohypoparathyroidism (PHP) type Ia. We studied the longitudinal growth of the short bones in the hand of a 15-yr-old girl with PHP type Ia who had been followed for congenital hypothyroidism. Radiographs of the hand of the patient, who had been X-rayed every year since 2 yr of age, were studied. She showed cone-shaped epiphyses of the hand at 2 yr of age before showing brachydactyly. At 4 yr of age, she showed brachydactyly and an advanced bone age, and some short bones were prematurely fused at 6 yr of age. The short bones without cone-shaped epiphyses were also short as a result of a disturbance of the longitudinal bone elongation. In conclusion, the brachydactyly of PHP type Ia is thus considered to be caused by both early epiphyseal fusion with cone-shaped epiphyses and a disturbance of the longitudinal bone elongation.

Three unrelated patients affected by a characteristic metaphyseal chondrodysplasia with cup-shaped metaphyses of the knees are described. Lower femoral and upper tibial cone-shaped epiphyses were embedded in the metaphyses. Main clinical features are short stature, shortening of the lower limbs, limitation of knee extension, and normal hands length. Radiographs of skull, spine, and hands showed no abnormality. This particular appearance of the knees has been seldom described in acquired disease such as repeated injuries, meningoccocemia, scurvy, and hypervitaminosis A. Metaphyseal dysplasias with these distinctive radiological findings of the knees are uncommon. Differential diagnosis includes trichoscyphodysplasia and acroscyphodysplasia among others. Two other cases reported by Kozlowski showed the most similarities to our three cases and defined a new form of metaphyseal dysplasia with specific lower limbs involvement and cup-shaped metaphyses. © 2003 Wiley-Liss, Inc.

Trichorhinophalangeal syndrome is a very rare genetic disorder, where damage and mutation to the number 8 chromosome affects sufferers in numerous ways. The syndrome has three types, all characterized by abnormally short stature, sparse hair, short deformed fingers with cone-shaped epiphyses visible in radiographs. Type I is the most common. Type II is characterized by the development of multiple bony exostoses and frequently, mental disability. Type III is a more severe form of type I and is associated with short stature. This report presents a 28-year-old man who had the characteristic features of type I with the presence of multiple erupted supernumerary teeth with normal mentation and karyotyping with high resolution G banding displayed normal chromosomal complements.

A new type of enchondromatosis is described with a symmetrical distribution but not involving the spine and characterised by severe ankle deformity, shortening of metacarpals and phalanges, and cone-shaped phalangeal epiphyses.

We report on a 5½ year-old Italian girl with a distinctive form of metaphyseal chondrodysplasia simulating cartilage hair hypoplasia. The pattern of metaphyseal changes and the associated bony abnormalities differentiate this patient from all the recognized forms of metaphyseal chondrodysplasia. © 2001 Wiley-Liss. Inc.

Saldino-Mainzer syndrome is part of a group disorders, the conorenal syndromes, that are characterized by cone-shaped epiphyses with chronic renal disease in childhood and are variously associated with retinitis pigmentosa, cerebral ataxia, and/or abnormalities of the proximal epiphyses and femur metaphyses. Saldino-Mainzer syndrome usually has sporadic presentation. The present report shows the unusual findings of a 23-year-old woman, affected by the Saldino-Mainzer syndrome and has undergone kidney transplantation, highlights the possible association with maxillofacial and cephalometric abnormalities.

A rare case of oral-facial-digital syndrome type I is presented. The patient had two features that have not been previously described: cone-shaped epiphyses in the toes and trifurcation of the soft palate.

Cartilage-hair hypoplasia is a rare, autosomal recessive skeletal dysplasia, caused by mutations in the RMRP gene. The skeletal abnormalities include irregular metaphyses and cone shaped epiphyses of the hands. Molecular diagnosis confirmed two novel RMRP mutations in a compound heterozygous state in two siblings with this condition.

Conorenal dysplasia is a rare sydrome which includes cone shaped epiphysis, renal disease in childhood, retinitis pigmentosa and abnormality of the proximal physis and metaphysis of the femur. A long term followup of one patient is presented along with a review of the reported cases. © 2007 Wiley-Liss, Inc.

Genetic disorders of the skeleton or skeletal dysplasias are a clinically diverse and genetically heterogeneous group of connective tissue disorders affecting skeletal morphogenesis and development.1–4 More than 200 different entities have been described.5 Despite the growing availability of molecular testing for several of these disorders, the diagnosis of a skeletal dysplasia still relies primarily on a thorough clinical and radiographic study of the patient.6 Some particular radiographic signs can be very helpful in establishing the diagnosis. One such example is the presence of cone shaped epiphyses.7 In most instances, cone shaped epiphyses represent the initial stage of premature epimetaphyseal fusion resulting in growth arrest and shortening of the bone involved. Analysis of the site and shape of cone shaped epiphyses, in particular of the phalanges, can be helpful in the diagnosis of skeletal dysplasias.8–10 Based on the observation of four patients, we delineate a new skeletal dysplasia with autosomal recessive inheritance. Because all cases show cone shaped epiphyses in the hands and a radiographically characteristic involvement of the proximal femoral epiphyses, we propose naming this condition acrocapitofemoral dysplasia. ### Patient 1 Patient 1 was referred at the age of 9.5 years with the tentative diagnosis of hypochondroplasia. She was born at 34 weeks’ gestation with a birth weight of 2470 g (50th centile) and length of 47 cm (50th-90th centile). The pregnancy was uncomplicated and the delivery uneventful. Around the age of 7 years, short stature was noted. She had normal psychomotor development but experienced emotional problems related to her short stature. The parents are healthy but consanguineous (fig 1A). The father measures 166 cm and the mother 163 cm. A younger sister is also healthy and has a normal height. Physical examination at the age of 9 years 6 months showed short stature with height …

A pair of monozygotic twin girls with trichorhinophalangeal syndrome type I (TRPS I), followed from 8.3 to 16.1 years of age, is described. Both showed typical dysmorphic features and severe short stature, but only one had Perthes-like changes in the right capital femoral epiphysis. The radiographic findings and evolutionary changes of phalangeal cone-shaped epiphyses (PCSE) of the hands are illustrated in this report. The unusual bone maturation and growth of the twins are also described. Both presented poor growth and delayed bone age until about 13 years, followed by marked acceleration of bone age and stunted pubertal height spurt.

SUMMARY Two sibling girls with cone-shaped knee epiphyses and metaphyses are described. Bone dysplasia with this rare, distinctive, radiographic finding, was first reported by Bellini and Bardare with only few cases reported thereafter. Velores et al. divided bone dysplasias with cone-shaped epiphyses and metaphyses of the knee in two entities which they named trichoscyphodysplasia and metaphyseal acroscyphodysplasia. Although the authors agree that there is more than one bone dysplasia that presents with these distinctive radiographic knee appearances, they consider that too few cases have been reported to satisfactorily classify this group of disorders.

A girl with slowly progressive difficulty in walking, dysarthria, growth retardation, brachydactyly, and cone shaped epiphyses is described. This constellation of symptoms was described in 1987 by Fitzsimmons and Guilbert. It probably represents a rare mendelian disorder of unknown cause.

Male uniovular twins presented at the age of 20 years with spastic paraplegia which had been slowly progressing over the years. Both have skeletal anomalies of their hands and feet with brachydactyly, cone shaped epiphyses, and an abnormal metaphyseal phalangeal pattern profile. In addition, they have a non-specific dysarthria and low-normal intellectual ability.

Cone-shaped epiphyses (CSE) are reported in left-hand radiographs of a sample of 1,399 otherwise normal Japanese children aged 5-11 years. CSE occurred in only three centers: distal thumb, mid-index finger, and mid-fifth finger. The overall frequency of 23% shows a female bias (32% to 16%), which disappears when mid-5 cones are excluded. Chi-squared analyses show significant gender bias for mid-5 cones alone or in combination with the other phalanges, and show significant center associations: CSE in distal-1 and/or mid-2 are more common in association with mid-5 cones than they are without mid-5 cones. The CSE female bias in mid-5 is essentially unchanged across age-cohorts when bone-age is controlled for precocity, and no significant trends in CSE frequency with age are noted for either gender.

Die Autoren beschreiben 6 Falle von „Zapfenepiphyse“. Sie beobachteten diese eigenartige enchondrale Ossifikationsstorung nach Dyschondroplasie, enchondraler Dysostose, Osteomyelitis und nach Frakturen der Epiphyse. Auf Grund der beschriebenen Falle und experimentellen Beobachtungen sehen die Autoren die Ursache des Entstehens dieser Deformitat in einer Kreislaufstorung im Gebiete der epiphysaren und nutritiven Hauptarterie. Das Weiterwachsen des peripheren Teils des Wachstumsknorpels wird durch die periosteale und perichondrale Blutversorgung gesichert. Das mit der Deformitat verknupfte Zuruckbleiben im Wachstum hangt vom Grad der enchondralen Ossifikationsstorung bzw. Verletzung ab.

We report a 4.5 year old Egyptian male child, fourth in the order of birth of healthy remote consanguineous parents. He has typical facial as well as skeletal features of Trichorhinophalangeal syndrome (TRPS) II. The facial features included bilateral downward slanting palpebral fissures, bulbous nose, long filtrum, retromicrognathia, sparse hair in the scalp and thick eyebrows. The skeletal features included retarded bone age, cone shaped epiphyses of the phalanges and multiple exostoses. The patient has also growth retardation, moderate mental retardation and hyperlaxity of the right knee joint. However our patient has some features not reported in TRPS II patients. These included bilateral partial ptosis, long eye lashes, preauricular skin tag, short 2nd right finger, short metacarpals of both thumbs. So we have to expand the clinical spectrum. Karyotype demonstrated 46,XY,del 8(q23.3-q24.1). Keywords: Trichorhinophalangeal syndrome; Langer–Giedion syndrome; Exostosis; Short stature; Cone shaped epiphyses

We report three cases of tricho-rhino-phalangeal syndrome (TRPS) type I in a Belgian family. They presented typical characteristics such as a pear-shaped nose, and short, deformed fingers with cone-shaped epiphyses of some middle phalanges of the hands. Hair growth was practically normal in our patients, except for some narrowing of the lateral part of the eyebrows. Perthes-like hip dysplasia was documented in two of our cases. The proband presented at the age of 31 with Kienboch's disease of the right wrist. Blood and urine analysis showed no clear anomalies. In this patients, echography revealed a renal cyst containing a stone. The relationship of these findings to TRPS is discussed.

A case of metaphyseal dyschondroplasia is reported with the unusual feature of cone-shaped epiphyses of the tibiae and bones of the hand. An 8-year-old boy (born June 1972) was admitted in 1980 having had bowed lower limbs since the age of 4 years. The child showed reduction in stature and weight but had normal mental development. The limbs and hands were short compared with the trunk. No visceral abnormality or alopecia was present. The bilateral genu varum and genu recurvatum were considered to be secondary to the abnormal length of both fibulae. Consequently, bilateral fibular resection was performed in December 1980 and the genu varum became stabilised. We saw the child for the first time in October 1984, when dwarfism was marked. His height was 1.08 m (− 7 SD) and his weight was 21.95 kg (− 3 SD) at an age of 12 years and 4 months. At birth his weight had been 2.95 kg and he measured 47 cm in length. He had suffered from no significant disease during childhood and, in particular, had not had meningoc...

The form of epiphyseal-diaphyseal dysostosis in the phalanges of the hand having the appearance of a cone-and-crater (cone-shaped epiphysis) is a common variant in otherwise normal individuals. Dysplasia on the radial margins of the epiphysis and diaphysis, typically resulting in clinodactyly, is another variant and is also common in Down's syndrome. Both variants frequently involve brachymesophalangia. The strong female bias in cone epiphyses and the lack of such bias in dysplasia not involving cones has led to the interpretation of distinct etiologies for the two patterns. A single case displaying brachymesophalangia with cone epiphysis in the middle phalanx of the left fifth finger and brachymesophalangia with clinodactyly in the corresponding bone of the right hand is reported. This is evidence that in certain cases the two patterns of mid-5 dysostosis are manifestations of the same condition.

The phalangeal cone shaped epiphysis of the hands (PhCSEH1) observed in the extended Saldino-Mainzer syndrome (SMS), including nephronophthisis, are typed in accordance with standard tables. Of the more than 40 known types, type 28 and/or 28A were found in all eight cases available for analysis, frequently also associated with types 38, 38A, 37 and others. Similar PhCSEH are also observed in asphyxiating thoracic dysplasia (ATD), as well as in some cases of peripheral dysostosis combined with dwarfism. The striking similarity of the PhCSEH formula in our eight cases and of some cases of ATD, all suffering from chronic renal disease, suggests a common pathogenetic pathway of these conditions. The collective name of “conorenal syndromes” is suggested.

A report is presented of a brother and sister with an uncommon oculorenal syndrome consisting of a hereditary renal disease (familial nephronophthisis), retinitis pigmentosa, cerebellar ataxia, and skeletal anomalies. The bony changes in the boy consisted of pronounced cone-shaped epiphyses of middle phalanges of hands and feet and irregular ossification of femoral heads and necks. Cone-shaped epiphyses and other such minor skeletal anomalies may call attention to associated unsuspected visceral disease, frequently renal.