Michaeli D, Rajendra R, Kim DC, Goodlett MD, Humphries JR, Nimityongskul P. Schmid Type Metaphyseal Chondrodysplasia in a Large Single Genetic Lineage. J Human Clin Gen. (2021);3(1):1-8 Journal of Human & Clinical Genetics Research Article Open Access

Schmid Type Metaphyseal Chondrodysplasia in a Large Single Genetic Lineage David Michaeli, Ravi Rajendra, Daniel C. Kim, Michael D. Goodlett, John R. Humphries, Prasit Nimityongskul Department of Orthopaedic Surgery, University of South Alabama, Mobile, AL, USA

Article Info Abstract

Article Notes Several subtypes of metaphyseal chondrodysplasia exist, of which the Received: March 03, 2021 Schmid type is the most common. Characteristics include short limbed Accepted: May 08, 2021 , , genu vara, and waddling gait. Skull, spine, and upper *Correspondence: extremity involvement is minimal and often nonexistent. The primary defect Dr. David Michaeli, Department of Orthopaedic Surgery, involves a mutation affecting the metaphyseal portion of the growth plate, University of South Alabama, Mobile, AL, USA; Email: while the epiphysis is normal. A large single lineage family with metaphyseal [email protected]. chondrodysplasia, Schmid type (MCDS) was investigated. A genetic pedigree of 135 members of this family showed autosomal dominant inheritance between ©2021 Michaeli D. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License. all 42 affected members. The large sample size allowed for the characterization of a broad range of features present in cases of MCDS. The majority of affected Keywords: patients exhibited coxa vara with an average neck/shaft angle of 105 degrees. Metaphyseal chondrodysplasia Despite coxa vara, premature osteoarthritis of the is not a feature of MCDS. Schmid Type is the most prevalent disorder in this group, but greater MCDS than 30% of patients may exhibit . This manuscript highlights pedigree dwarfism MCDS background information, differential diagnoses, treatment options, and prognosis to aid in clinical decision-making.

Introduction Metaphyseal chondrodysplasias (MCD) represent an array of conditions that present complex challenges for orthopaedic surgeons, as potentially, all long can be affected in unison.1

and shortening of the tubular long bones with widened epiphyseal plates.Radiographs Widespread reveal irregularitiescoxa vara results including in the splaying, quintessential flaring, waddling cupping, gait seen in patients (Figure 1). Sclerosis, and less commonly, vertebral platyspondyly and hand involvement may be present. In addition, pain has been reported in the past.2 Schmid metaphyseal dyschondroplasia (MCDS) is an inherited 3 Historically, MCDS was radiographically characterized by irregularities of the long- bonemetaphyseal metaphases disorder with first normal described hand andin 1949. vertebral development. Spine involvement was evident in scattered cases, but often resolved4 as patients aged.5 Today, MCDS is described as the development of progressive short stature with features usually absent at birth. Clinical characteristics manifest in early childhood with short limbs, genu varum, and waddling gait (Figure 2). Facial features and head size are typically normal, but adult height is several standard deviations below the mean, with a wide spectrum throughout affected individuals. Extraskeletal manifestations are absent, and affected individuals display normal intelligence.2 MCDS is caused by a mutation of the COL10A1 gene, which is transmitted in an autosomal dominant mode of inheritance. This

Page 1 of 8 Michaeli D, Rajendra R, Kim DC, Goodlett MD, Humphries JR, Nimityongskul P. Schmid Type Metaphyseal Chondrodysplasia in a Large Single Genetic Lineage. J Journal of Human and Clinical Genetics Human Clin Gen (2021);3(1):2-8

obscured. It is also the most common of the inherited metaphyseal chondrodysplasias, occurring at an estimated rate of three to six cases per million, which some current authors believe is a profound underestimation.6,7 Other, rarer metaphyseal chondrodysplasias with similar features to those of MCDS should be considered among the differential diagnoses. These include Jansen type, McKusick type (Cartilage–Hair Hypoplasia –CHH), and MCD with Malabsorption and Neutropenia (Shwachman Diamond Syndrome –SDS). CHH and SDS have additional multi-system involvement. Meticulous assessment of the patient, including judicious scrutiny of radiographs and analysis of complete laboratory markers, is crucial to avoid misdiagnosing these complex conditions with rickets.8 Regarded as the most severe subtype, Jansen metaphyseal chondrodysplasia (JMC) is a rare autosomal-dominant disease caused by activating mutations of PTHR1 resulting in inhibition of chondrocyte hypertrophic differentiation. Features of this disorder are more profound than those of6,9 Figure 1. AP radiograph of pelvis and proximal femur in a known MCDS and are detected at birth.6 In infancy, osteopenia, MCDS patient. The typical decreased neck-shaft angle (coxa vara) is subperiosteal erosions, and hypercalcemia may cause seen (red). Furthermore, decreased articulo-trochanteric distance confusion with hyperparathyroidism.10 Patients exhibit (distance between tangential lines about the superior acetabular marked growth plate abnormalities, short stature and articular surface and superior pole of the greater trochanter) accompanies the coxa vara deformity (blue). Splaying and flaring of bowing of long bones, micrognathia, , and the growth plates is evident. premature closure of cranial sutures. 9 Cartilage–hair hypoplasia (CHH) is a rare autosomal recessive metaphyseal chondrodysplasia caused by mutations of the untranslated RMRP gene. It is characterized by short stature with a spectrum of skeletal

that can lead to recurrent infections.11 In the newborn, the abnormalities, fine sparse hair, and immune deficiency metaphyseal changes only apparent after four months of age.first12 sign is bowing of the femora which is diagnostic, with Similar to CHH, Shwachman Diamond Syndrome affects multiple organ systems. A mutated SBDS gene on chromosome 7, normally involved in ribosome biogenesis and mitotic spindle stabilization, is disrupted, leading to the disease manifestation.13 Besides the immune, gastrointestinal, and cardiac features, SDS patients commonly exhibit skeletal abnormalities. Uniquely, these bony changes are due to failure of the columnar cartilage cells to hypertrophy.12 The primary defects involve abnormal development of growth plates, most frequently 1. the femoral head. Figure 2. AP radiograph of knee and tibia in a known MCDS patient. abnormalities, metaphyseal14 dysostosis, osteopenia, and Genu varus with irregularities in the growth plates can be seen slipped capital femoral Otherepiphysis findings (SCFE). include15 cage bilaterally. Patients with metaphyseal dysmorphisms may present mutation quantitatively reduces collagen type X production, a challenging clinical diagnosis to healthcare providers. thereby reducing its presence at the hypertrophic zone The differential diagnoses can be numerous, but special adjacent to calcifying cartilage.1 care must be taken to differentiate chondrodysplasias from the process by which long bones elongate, is ultimately rickets. In an attempt to reduce overall morbidity, evaluation Endochondral ossification,

Page 2 of 8 Michaeli D, Rajendra R, Kim DC, Goodlett MD, Humphries JR, Nimityongskul P. Schmid Type Metaphyseal Chondrodysplasia in a Large Single Genetic Lineage. J Journal of Human and Clinical Genetics Human Clin Gen (2021);3(1):3-8 of calcium and vitamin D is an essential component of initial Much of the research regarding MCDS occurs by studying index families, thus supporting the autosomal dominant transmission hypothesis.6 One such family has management. Vitamin D deficiency is then subcategorized16 Recognition ofinto metaphyseal severe deficiency chondrodysplasia (<5 ng/mL), and moderate differentiation deficiency from (5- arguably one of the largest regarding this disease pattern rickets15 ng/mL), is essential and insufficiency due to contrasting (16-20 ng/mL). clinical treatments. inbeen the identified literature. by our institution, and our investigation is While vitamin D supplementation is the remedy for rickets, it may precipitate toxicity in patients with MCDS.12,16,17 Materials And Methods A large, single family affected by this disorder had been the lower extremities. Regarding gait, waddling is suggested noticed by our institution when the orthopaedic surgery Orthopaedic treatment in MCDS is primarily confined18 Patients to department began rendering services to the state Children’s have decreased articulo-trochanteric distance (ATD) Rehabilitation Service (previously Crippled Children’s resultingto be caused in decreased by insufficient gluteal gluteal mechanical muscles. advantage. Clinic). Forty-two members of this family exhibited MCDS Usually, the entire femur shows a varus bow with the19 and underwent a thorough history, physical exam, as well as clinical appearance of genu varum. In some patients, varus radiographic follow-up for a minimum of twenty years All alignment may improve spontaneously during childhood. affected members manifested radiographic signs of MCDS. There were no breaks in the hereditary link or skipped Some indications for surgical correction include generations. There was no history of consanguinity in the family. femoral neck, and progressive deformity. Unfortunately, recurrencesignificant coxaof vara,deformity a triangular with fragmentlongitudinal in the inferiorgrowth The following clinical measurements were obtained is common in many patients who have undergone on each affected individual of the family: standing height, surgical treatment. Guided growth procedures, such as sitting height, span length, angulation of the knee, hemiepiphysiodesis using eight-plates or stapling, may and hip range of motion (Table 1). Normal height was improve angular deformities in some children.20,21,22 established using data from the National Health Survey

Table 1. Age, sitting/standing height, arm length, knee alignment, and radiographic characteristics of the 42 family members with MCDS evaluated in the study. Comments refer to relevant orthopaedic procedures undergone by patients prior to the study. Hip Hip Height Sitting Hip Neck Shaft Name Arm Span Knee Internal External No. Standing P Height P A b d u c ti o n Angle Comments Age/Sex (in/cm) Alignment R o t a ti o n R o t a ti o n (in/cm) (in/cm) R L R L R L R L M.S. 55 32 56.5 1 0 0 Varus 0 15 20 5 25 15 80 90 60+1 F 139.7 81.28 143.51 I.K. 62.5 34 62 2 0 0 Valgus 0 5 35 30 30 28 135 135 68+4 M 158.75 86.36 157.48 J.K. 59 33 63 3 0 0 Varus 13 9 40 30 30 35 100 120 63+8 M 149.86 83.82 150.02 C.K. 59.5 32 60 4 0 0 Valgus 5 23 35 27 30 30 110 110 48+1 M 151.13 81.28 152.14 M.K. 64.5 34 72.5 5 2 0 Straight 15 15 50 50 35 35 105 110 60+10 M 163.83 86.36 184.15 E.M. 48.5 26.5 53 6 0 0 Valgus 40 27 15 26 35 32 100 105 60+10 M 123.2 67.3 134.6 A.S. 60.75 33 53.25 7 7 10 Straight 30 30 30 30 30 20 90 90 30+11 F 154.31 83.82 158.11 E.C. 58 31.5 60 8 0 0 Valgus 27 27 30 40 30 20 95 95 38+6 F 147.32 80.01 152.4 A.R. 61.5 33 65 9 10 10 Valgus 10 10 55 55 25 25 100 100 29+7 F 156.21 83.82 165.1 C.S. 61 33.5 66.75 10 0 0 Valgus 25 30 20 45 40 40 87 87 44+6 M 155 85.1 169.6 N.D. 51 30 55.5 11 0 0 Varus 11 18 50 50 20 20 90 92 26+2 F 129.54 76.2 140.97 I.K. 61.5 31 66 12 0 0 Straight 15 15 35 35 35 35 115 115 34+8 M 156.21 78.74 167.64 N.M. 57.5 28.5 60 13 30 5 Valgus 8 8 82 82 35 35 100 100 11+11 M 146.05 72.39 152.4

Page 3 of 8 Michaeli D, Rajendra R, Kim DC, Goodlett MD, Humphries JR, Nimityongskul P. Schmid Type Metaphyseal Chondrodysplasia in a Large Single Genetic Lineage. J Journal of Human and Clinical Genetics Human Clin Gen (2021);3(1):4-8

N.M. 59 32 62 14 0 0 Valgus 15 15 55 55 32 32 105 105 27+1 F 149.86 81.28 157.48 R.K. 56.74 32 61 15 0 0 Varus 10 10 30 30 35 35 107 110 31+0 F 144.15 81.28 154.94 J.K. 56 29.25 59 16 10 10 Valgus 12 12 25 35 30 30 105 105 12+4 M 142.24 72.29 149.86 C.K. 60 31.5 61 R Valgus 17 7 0 12 15 60 38 32 30 107 123 16+3 F 152.4 79.38 154.94 L Varus L.K. 59.5 31 64 18 1 0 Valgus 35 35 32 27 28 25 105 105 18+4 F 151.13 78.74 162.56 R.K. 64.5 33 67 19 2 0 Varus 30 30 55 55 40 40 107 107 41+3 M 163.83 83.82 170.18 R.K. 67 34 74 20 15 0 Varus 35 35 30 30 43 43 112 112 36+4 M 170.18 86.36 187.96 T.P 34.5 23 40 21 0 5 Varus 35 35 35 35 25 25 107 107 5+6 F 87.63 58.42 101.6 M.P. 45 26 47.5 22 2 20 Varus 25 25 30 30 34 34 110 110 7+9 F 114.3 66.04 120.65 L.J. 59 34 61 R Varus 23 0 25 30 25 30 25 25 25 90 88 34+9 F 149.86 86.36 154.94 L Straight K.M. 48.5 26 47.25 Bilateral Valgus Hip 24 0 0 Valgus 26 26 65 65 45 45 140 135 10+6 F 123.2 66 120 Osteotomies E.K. 41.75 22 45.5 25 0 0 Varus 12 12 35 35 40 40 110 110 6+7 M 106.05 55.88 115.57 R.K. 33.5 20.5 33.75 26 5 25 Varus 15 15 4 40 45 45 123 123 2+4 M 85.09 52.07 85.73 A.K. 42.75 25 46 27 0 7 Varus 10 10 40 40 30 30 110 110 7+7 F 108.59 63.5 116.84 D.K. 31.5 18.75 32.5 28 0 0 Varus 10 10 30 30 35 35 122 122 2+6 F 80.01 47.63 82.55 K.K. 24.75 17 26.5 29 0 25 Varus 15 15 65 65 40 40 125 127 0+9 F 62.87 43.15 67.31 R.K. 46.25 25 47.23 30 45 25 Valgus 65 65 55 55 43 43 117 117 6+2 M 117.48 63.5 120.02 S.K. 35 21.5 34.5 31 75 75 Varus 55 55 65 65 40 40 115 110 2+5 F 88.9 54.61 87.63 R.J. 49.5 30 53 32 50 50 Varus 20 0 15 25 20 15 95 110 10+10 M 125.73 76.2 134.62 B.C. 59 32.75 61 33 10 10 Varus 10 20 45 45 35 35 87 90 17+5 F 149.86 83.19 154.94 F.C. 59 34 60.5 34 0 2 Valgus 10 10 42 42 35 30 80 90 19+6 M 149.86 86.36 153.67 Bilateral Valgus Hip L.S. 62 37 67 35 0 65 Straight 45 37 25 37 50 50 130 146 Osteotomies 17+3 M 157.5 94 170.2 Tibial Osteotomies R.S. 59 31.5 59 Bilateral Valgus Hip 36 0 0 Varus 30 45 30 30 30 42 105 105 17+8 150 80 150 Osteotomies E.S. 59 32.5 62 R Valgus Bilateral Valgus Hip 37 0 0 25 30 45 50 45 45 100 105 15+8 M 150 82.6 157.5 L Straight Osteotomies B.M. 54.5 28.5 56 38 2 1 Varus 10 10 45 45 35 35 102 102 12+8 M 138.43 72.39 142.24 C.M. 49.5 26.25 51.5 39 0 0 Varus 15 15 50 50 30 30 105 105 12+1 F 125.73 67.31 130.81 R.K. 41 23 43.5 40 0 0 Varus 10 0 30 40 22 22 100 100 6+4 M 104.14 58.42 110.49 T.K. 34 20 34 41 5 5 Varus 15 15 40 40 32 32 125 124 2+7 M 86.36 50.8 86.36 31 17.5 30.5 42 L.K. 6 5 Varus 15 15 40 40 30 30 123 123 78.745 44.45 77.47

Page 4 of 8 Michaeli D, Rajendra R, Kim DC, Goodlett MD, Humphries JR, Nimityongskul P. Schmid Type Metaphyseal Chondrodysplasia in a Large Single Genetic Lineage. J Journal of Human and Clinical Genetics Human Clin Gen (2021);3(1):5-8 of height at skeletal maturity. A standard AP pelvis x-ray Short stature is the main clinical presentation with a study as well as AP x-rays of both were taken in all affected individuals. Protrusio acetabuli was diagnosed and men, respectively. Overall average height for both using Kohler’s line. Evidence of iliac wing hypoplasia was malesaverage and standing females height in skeletally of 145.6 cmmature and 156.9 MCD cmSchmid in women type subjectively judged by the senior author. is 151 cm (Table 2). The shortness of stature compared to Results

All individuals presented in our study manifest isthe at normal the 5th population percentile. is statistically significant (p<0.001). characteristic features of MCDS. The pedigree supports The average standing height of the 42 patients in this study an autosomal dominant inheritance pattern (Figure 3). The difference in sitting height (Table 3) of the MCDS

I

II

III

IV

V

Figure 3. Pedigree representation of the MCDS cases within five generations of the study family. 135 members were investigated. 58 reportedly exhibited MCDS features, but only 42 participated in the study. Participants are numbered 1 through 42. Completely shaded shapes (n = 42; male = 21, female = 21) are affected individuals who were examined. Unshaded are those who were normal and examined (n = 50; male = 31, female = 15). Shaded shapes with white patterned dots represent individuals reportedly affected but not examined (n = 16; male = 9, female = 7). Unshaded shapes with black patterned dots represent individuals reported normal, but not examined (n = 27; male = 12, female = 15). A line through a shape (shaded or not) represents a deceased individual.

Table 2. Average standing height in skeletally mature participants with MCD - Schmidt Type (Age 16 and above) compared to normal average standing height in United States. The difference in standing height between MCD and normal population is statistically significant at P < 0.001. Number of Patients Avg. Standing Height inch (cm) Range inch (cm) SD MCD-Schmidt type: 57.33 48.5 - 61.5 3.97 12 Female, age > 16 (145.63) (123.2 - 156.21) (10.1) Unaffected: 63.86 2.36

Female (US), age > 16 (162.2) (6.0) MCD-Schmidt type: 61.77 59.0 - 67.0 2.68 11 Male, age > 16 (156.9) (149.86 - 170.18) (6.8) Unaffected: 68.39 2.61

Male (US), age >16 (173.7) (6.64) MCD-Schmid type: 59.46 48.5 - 67.0 4.04 23 Female & Male, age > 16 (151.02) (123.2 - 170.18) (10.26)

Table 3. Average sitting height in skeletally mature participants with MCD-Schmid type (age 16 and above) compared to normal average sitting height in the United States. The difference in sitting height between MCD and unaffected population is statistically significant at P < 0.001. No. Avg. Sitting Height inch (cm) Range inch (cm) SD MCD-Schmidt type: 31.6 26.5 - 34 1.92 12 Female, age > 16 (80.26) (67.31 - 86.36) (4.88) Unaffected: 33.82 1.3

Female (US), age > 16 (85.9) (3.3) MCD-Schmidt type: 33.4 31 - 37 11 Male, age > 16 (84.84) (78.74 - 94) Unaffected: 36.02 1.22

Male (US), age >16 (91.5) (3.1) MCD-Schmid type: 32.44 26.5 - 37 1.96 23 Female & Male, age > 16 (82.38) (67.3 - 94) (4.98)

Page 5 of 8 Michaeli D, Rajendra R, Kim DC, Goodlett MD, Humphries JR, Nimityongskul P. Schmid Type Metaphyseal Chondrodysplasia in a Large Single Genetic Lineage. J Journal of Human and Clinical Genetics Human Clin Gen (2021);3(1):6-8 patients compared to the normal population is also highly patients in the study were below the 10th percentile in heightstanding (Tables height 4 and – 7). sitting On average, height, respectively90% and 79% (Table of MCDS 8) thesignificant skeletally (p<0.001). mature group, The the mean arm sitting span is height7.25 cm for longer the Radiographically, all but seven study subjects thanentire the study standing group height of patients in females is at and the 8.83 9th cm percentile. longer than In the standing height in males, with the entire study group demonstrated coxa vara with an average neck shaft angle of 105 degrees. Two additional individuals presented with averaging a 6.48 cmTable difference 4. Average in sitting arm span height and as astanding percentage of average standing height of study participants. Sit Ht x 100% No. Range S.D. Stand Ht Female, age > 16 12 55.15 52.1 - 58.8 2.21 Male, age > 16 11 54.06 50.4 - 59.7 2.89 Female & Male, age > 16 23 54.63 50.4 - 59.7 2.56 Female, age < 16 9 59.56 53.5 - 68.6 5.27 Male, age < 16 10 55.27 49.6 - 61.2 3.88 Female and male, age < 16 19 57.3 49.6 - 68.6 4.97 Entire series 42 55.84 49.6 - 68.6 4.02

Table 5. Average arm span in skeletally mature participants (age 16 and above) with MCDS. Number of Patients Avg. Standing Height inch (cm) nge inch (cm) SD inch (cm) MCD-Schmidt type: 60.19 53 - 64 3.51 12 Female, age > 16 (152.88) (134.6 - 162.56) (8.92) MCD-Schmidt type: 65.25 59 - 72.5 4.93 11 Male, age > 16 (165.68) (149.86 - 184.15) (12.52) MCD-Schmid type: 62.61 53 - 72.5 4.89 23 Female & Male, age > 16 (159.03) (134.6 - 184.15) (12.42)

Table 6. Difference in length between arm span and standing height in study participants. (Normal = < 3.5 cm). On average, participants’ arm span is greater than standing height, suggesting greater involvement in thelower extremities. No. Avg arm span – standing height inches (cm) Range inches (cm) SD. 2.85 1 – 4.5 1.34 Female, age > 16 12 (7.25) (2.54 – 11.43) (3.41) 3.48 -0.5 – 8.0 2.89 Male, age > 16 11 (8.83) (-1.27 – 20.32) (7.33) 3.14 -0.5 – 8.0 2.19 Female & Male, age > 16 23 (8.0) (-1.27 – 20.32) (5.56) 1.64 -1.26 – 5.2 2.03 Female, age < 16 9 (4.16) (-3.2 – 13.97) (5.16) 2.1 0 – 3.75 1.26 Male, age < 16 10 (5.32) (0 – 9.52) (3.21) 1.88 -1.26 – 5.5 1.66 Female and male, age < 16 19 (4.77) (-3.2 – 13.97) (4.23) 2.55 -1.26 – 8.0 2.08 Entire series 42 (6.48) (-3.2 – 20.32) (5.28)

Table 7. Arm span to standing height ratio in study participants (Normal 1.00 - 1.03). With lower extremities affected more than upper extremities, the arm span to standing height ratio is increased to a value greater than the normal mean. No. Arm Span/Standing Height Ratio Range S.D. Female, age > 16 12 1.05 1.02 - 1.09 0.027 Male, age > 16 11 1.05 0.99 - 1.12 0.04 Female & Male, age > 16 23 1.05 0.99 - 1.10 0.035 Female, age < 16 9 1.04 0.97 - 1.16 0.06 Male, age < 16 10 1.04 1.00 - 1.09 0.03 Female and male, age < 16 19 1.04 0.97 - 1.16 0.04 Entire series 42 1.05 0.97 - 1.16 0.04

Page 6 of 8 Michaeli D, Rajendra R, Kim DC, Goodlett MD, Humphries JR, Nimityongskul P. Schmid Type Metaphyseal Chondrodysplasia in a Large Single Genetic Lineage. J Journal of Human and Clinical Genetics Human Clin Gen (2021);3(1):7-8

Table 8. Proportion of study participants whose standing height and sitting height is at or belowth 5 and 10th percentile.25 No./Total Percent Participants with Standing Height at or Below 5th Percentile 26/42 62% Participants with Standing Height at or Below 10th Percentile 38/42 90% Participants with Siting Height at or Below 5th Percentile 23/42 55% Participants with Sitting Height at or Below 10th Percentile 33/42 79% neck shaft angles >120, but they had previously undergone shaft angle of 105 degrees. All study subjects declined valgus osteotomies. The normal femoral neck shaft angle elective surgery to correct bony alignment, gait deformity,

study population is from a single lineage with individuals evidenceis between of 125-135premature degrees, osteoarthritis and varus of the is definedhips in herethis whoand muscularare aware insufficiency. of the natural This progression is likely becauseof MCDS thein as ≤120. Follow-up radiographs of the showed no their family. Remarkably, despite this deformity, the vast hypoplasia. No evidence of protrusio acetabuli was seen in majority of our study population remained clinically anycondition. of the radiographs. In this study, 60% of patients exhibited iliac functional with very little limitation of activities. Premature osteoarthritis of the hips was not a notable feature in our In studies on MCDS, knee alignment is reported to be study population, and only one patient in his 60s showed evidence of osteoarthritis. Most of the study population, of the patients demonstrated genu varum, approximately in varus. In this series of 42 patients, approximately 50% however, did exhibit waddling gait due to weakness of the gluteus medius in the setting of coxa vara. of our population had straight knees. 33% demonstrated genu valgum, and approximately 10% Due to the breadth of our patient population, we were Patients in this series exhibited normal life spans with able to elucidate more patterns associated with MCDS. Previous accounts described predominantly genu varum congenital abnormalities of the musculoskeletal system wereno evidence seen caudal of detectable to the knees intellectual in these patients. deficits. No other with MCDS have genu varum.2 However, while our study Discussion populationpresentations consistently estimating demonstrated greater than coxa 60% vara of deformity patients proximally, variance in deformity occurred distally at the In this study, we describe the largest reported series of individuals of a single lineage who demonstrate varum, notably less than estimates in current literature. features consistent with MCDS. Short stature and knee. Of the 42 patients, only 50% demonstrated genu

23 Eighty-three suggestApproximately that diversity 33% of the of study deformity population can demonstratedoccur at the proximalpercent of femur the patients involvement, in our specificallystudy exhibited coxa these vara, two are kneegenu joint valgum and and must 10% be hadconsidered straight by knees. the orthopaedic Our results definingmain clinical characteristics features. Autosomal of this condition. dominant inheritance community in diagnosing and treating MCDS. of MCDS with no skipped generations was noted for the Conclusion The mean standing height of MCDS females and males 42 affected members in this large single lineage study. This is the largest reported series of a single lineage MCDS. Autosomal dominant mode of inheritance is comparison, the mean height of normal U.S. females and malesin our is study 162 cm was and 145 172 cm cm, and respectively. 156 cm, respectively. These results In lower extremities predominates compared to involvement ofconfirmed the trunk in or our spine. pedigree. The skull Subischial and upper involvement extremities in arethe relatively normal in these patients. Coxa vara is a consistent originalare both statisticallysample describing significant overall compared average to the standing normal heightpopulation for MCDS (p < individuals 0.001) and as consistent 150 cm. In with addition, Schmid’s our confers minimal lifestyle disability with no evidence for prematurefinding occurring osteoarthritis in the majority of the ofhips. our patients, The previously but this of the lower extremities rather than that of the axial established knee deformity in this condition is varus, but skeleton,findings confirm with an that average the short sitting stature to standing is due toheight dysplasia ratio our series revealed a third of patients with valgus knees. of 0.55, approximately two standard deviations higher The long-term follow-up reveals that these patients exhibit than normal individuals. with previous reports in24 the literature of minimal skull, Moreover,6 our findings agree spine, or trunk involvement. Referencesa normal life span in the setting of these findings. 1. metaphyseal chondrodysplasia as the result of a collagen type X defectWoelfle due JV, to Brenner a novel RE,COL10A1 Zabel nonsense B, Reichel mutation: H, Nelitz A M.case Schmid-type report of a patientsOur studypresenting confirms with coxa previous vara radiologicaland an average findings neck novel COL10A1 mutation. J Orthop Sci. related to proximal femur deformity with 83% of our 2011;16(2):245-249.

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10. Kozlowski K, Campbell2018;103(7):2660-2669. JB, Azouz ME, Sprague P. Metaphyseal chondrodysplasia, type Jansen. Australas Radiol. 23. 2008;28(6):632-639. type of metaphyseal chondrodysplasia and COL10A1 mutations-- 11. Sathishkumar D, Gach JE, Ogboli M, et al. Cartilage hair hypoplasia 1999;43(4):544-547. Mäkitie O, Susic M, WardAm L, J BarclayMed Genet C, GlorieuxA. FH, Cole WG. Schmid with cutaneous lymphomatoid granulomatosis. Clin Exp Dermatol. findingsFredriks inAM, 10 patients.van Buuren S, van Heel WJ,2005;137A(3):241-248. Dijkman-Neerincx RH, Verloove-Vanhorick SP, Wit JM. Nationwide age references for 12. 2018;43(6):713-717.Spranger JW. Metaphyseal chondrodysplasia. Postgrad Med J. 24. diagnostic value for disproportionate growth disorders. Arch Dis sitting height, leg length, and sitting height/height ratio, and their 13. 1977;53(622):480-487.Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS Child. are associated with Shwachman-Diamond syndrome. Nat Genet. 25. 2005;90(8):807-812. curves for children birth-18 years. United States. Vital Health Stat 11. Hamill PV, Drizd TA, Johnson CL, Reed RB, Roche AF. NCHS growth 2003;33(1):97-101.Topa A, Tulinius M, Oldfors A, Hedberg-Oldfors C. Novel myopathy 14. 1977(165):i-iv, 1-74.

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