Analyzing Effects of Sickle Cell Disease on Morphometric and Cranial Growth in Indian Population.

BACKGROUND: Sickle cell disease is the most pervasive autosomal recessive hereditary blood diseases and is characterized by the presence of sickle hemoglobin (HbS), which in turn gives rise to pathophysiological consequences. This HbS reduces the agility of erythrocytes plummeting their ability to pass through small vascular channels, which in turn results in increased blood viscosity and congestion of vascular beds, causing ischemia, local infarction, and hemolysis.
OBJECTIVES: The current study was conducted to carry out the morphometric analysis in patients with sickle cell disease.
MATERIALS AND METHODS: This study was conducted on 75 subjects detected with sickle cell disease aged between 8 and 16.5 years. The study involved 38 males and 37 females. All the subjects were subjected to lateral cephalogram for the calculation of various angular and linear dimensions of the craniofacial structures. The linear measurements made were nasion-menton height, anterior nasal spine (ANS)-menton height, and nasion-ANS height, whereas the angular measurements made were Frankfurt mandibular plane angle, Frankfort mandibular incisor angle, and incisor mandibular plane angle.
RESULTS: Major chunk of the subjects had retruded mandible and vertical growth pattern. Few subjects exhibited with maxillary protrusion.
CONCLUSION: It is concluded that early diagnosis and management of dental malocclusion in patients with sickle cell disease plays a pivotal role in an attempt to endow with a better quality of life to these individuals. Copyright:

INTRODUCTION

Hemoglobin is a protein having an oxygen binding affinity, is situated on the red blood cells. It has function of carrying oxygen molecules from the lungs to peripheral tissues and vice versa.[1] It is a hetero-tetramer comprising α-like and β-like globin subunits, each bound to a heme prosthetic group. Hemoglobin A is the most common form containing two alpha subunits and two beta subunits (α2β2).[2] Sickle hemoglobin is formed by the substitution of one amino acid (valine) for another amino acid (glutamic acid) at the 6th position of the beta-globin chain. This substitution is caused by a mutation in codon 6 within the β-globin gene on chromosome 11, where the sequence GAG occurs instead of GTG.[3]

Dating back to 1910, an American physician named James B. Herrick was the first to report the existence of atypical elongated and sickle-shaped erythrocytes in the peripheral smear of an anemic West Indian student who presented with leg ulcers, dyspnea, and icterus.[4]

As mentioned above, this abnormal positioning results in the formation of polymers, which are characteristically long and insoluble causing the red blood cells to become “sickle” shape. This phenomenon reduces the agility of erythrocytes plummeting their ability to pass through small vascular channels, which in turn results in increased blood viscosity and congestion of vascular beds, causing ischemia, local infarction, and hemolysis.[5]

Patients usually complain of severe incapacitating pain in the long bones, chest, back, abdomen, and pelvis, with no inflammation or swelling. Pain results from incitement of nociceptive nerve fibers allied to microvascular occlusion and bony infarcts. The pain may commence by the age of 6 months and is characterized by pain and swelling of the extremities. This condition is referred to as dactylitis or hand–foot syndrome. Vaso-occlusive crisis may also affect other organs such as lungs causing chest syndrome, brain causing stroke, and penis causing priapism. Other factors that may trigger the crisis state include dehydration, thermal changes in body, infection, or hypoxia caused by stress or exercise.[6]

The patients usually present with features anemia caused by intravascular hemolysis, resulting in abridged lifespan of the anomalous red blood cells. Anemia may deteriorate during vaso-occlusive crisis, due to the increase in the rate of hemolysis, Parvovirus B19 infection, and pooling of blood in the liver or spleen. Micro-infarcts may have an effect on the spleen, kidney, skeleton, and central nervous system. Obstruction in the spleen may render it nonfunctional, making the patient more susceptible to infections caused by microorganisms such as Streptococcus pneumoniae, Escherichia coli, Haemophilus, and Meningococcus. Bony infarcts may cause bone and joint destruction, predominantly in load-bearing areas, and can lead to osteomyelitis of the femoral or humeral head. Involvement of the central nervous system may cause stroke and may be linked with convulsions or other neurological deficits. Miscellaneous complications include retinal vascular changes, leg ulcers, cholelithiasis, retarded growth, and delayed puberty.[7]

Sickle cell disease is mainly characterized by expansion of bone marrow and proliferation throughout the skeletal system to compensate for the increased rate of hemolysis. Erythropoietic expansion or diploic expansion can also be seen in cranial bones. In the cranial vault, the diploic spaces increase accompanied by thinning of the outer ectocranial tables, resulting in clinically evident frontal and parietal bossing. Although rare, altered trabecular pattern gives a characteristic hair-on-end appearance.[8]

Oral and craniofacial manifestations

These patients have a high caries incidence due to alteration in enamel and dentin formation and calcification, frequent use of supplements containing sucrose, etc., and also have a higher disposition to developing periodontal disease, which may be attributed to the normal flora in the mouth, and changes in the cellular and humoral immune response.

Other nonpathognomic features of the disease include mucosal pallor, delayed tooth eruption, depapillated tongue, hypomaturation or hypomineralization of enamel and dentin, presence of pulp stones, asymptomatic pulpitis/pulp necrosis, hypercementosis, and craniofacial bone abnormalities. The maxilla tends to be adversely affected in sickle cell disease. It is characterized by prominence of the maxilla and malocclusion referred to as gnathopathy, which is liable to worsen with age in untreated cases. The erythropoietic expansion of the maxilla may cause flaring of the maxillary incisors.[9] These patients present with extraoral features such as a convex profile, depressed nose, prominence of zygomatic bone, lip incompetence, long face, and vertical maxillary excess.

The current study was conducted to carry out the morphometric analysis in patients with sickle cell disease.

MATERIALS AND METHODS

This study was conducted on 75 patients aged between 8 and 16.5 years (38 males and 37 females). All the participants were subjected to a screening program. The study was approved by the Research Ethics Committee, and a signed consent was obtained from every participant. These patients had been diagnosed by a thorough laboratory screening and the subjects who had undergone any orthodontic treatment or intervention and/or orthognathic or facial surgery were excluded from the study.

All the subjects were subjected to lateral cephalogram which were used to obtain angular and linear measurements of anatomic structures displayed. All markings and measurements were traced manually by a single examiner using an acetate paper. A sheet of acetate paper was positioned over the radiograph, and tracings were completed using a 0.5-mm pencil under illumination.

The following linear and angular measurements were done:

Nasion-menton height (mm): Vertical height between nasion – the most anterior point of the frontonasal suture in the midsagittal plane – and menton – the lowest point on the lower border of mandibular symphysis. This is an indicator of the anterior facial height

Anterior nasal spine (ANS)-menton height (mm): Vertical height between ANS projection formed by the fusion of the two maxillary bones at the intermaxillary suture and menton

Nasion-ANS height (mm): Frankfurt mandibular plane angle (FMA) is formed by the intersection of the Frankfort horizontal (FH) plane and the mandibular plane. FH plane is between the highest point on the superior margin of the external acoustic meatus and the most inferior point on the lower margin of the orbit. An FMA of 25° ±5° is within normal range

Frankfort mandibular incisor angle (FMIA) is obtained by the intersection of the long axis of the lower incisor with the FH plane. An FMIA of 65° ±5° is within normal range

Incisor mandibular plane angle (IMPA) is obtained by drawing a line through the apex and insical edge of the mandibular central incisor, extending it to intercept the mandibular plane. An IMPA of 90° ±5° is within normal range.

All the measurements were repeated after 15 days to minimize any error. The readings were recorded in master chart, and the data analysis was carried out statistically.

RESULTS

The present study comprised 75 patients aged between 8 and 16.5 years. The study comprised 38 males and 37 females.

The mean of the nasion-menton height for age group of 7.5–10.5, 10.6–13.5, and 13.6–16.5 (male and female) years was 114.29 mm and 120.42 mm; 121.32 mm and 118.38 mm; and 120.89 mm and 118.58 mm, respectively. The mean of the ANS-menton height for age group of 7.5–10.5, 10.6–13.5, and 13.6–16.5 (male and female) years was 72.83 mm and 75.62 mm; 73.06 mm and 69.84 mm; and 71.85 mm and 72.880, mm respectively. The mean of the nasion-ANS height for age group of 7.5–10.5, 10.6–13.5, and 13.6–16.5 (male and female) years was 52.1 mm and 50.89; 49.48 mm and 50.07 mm; and 50.54 mm and 50.25 mm, respectively [Table 1].

Table 1

Results of one sample t-tests, by gender, and comparison of absolutes mean Z-scores between genders of anterior face height in mm

Variable	Age group	Male			Female			Sex with larger Z-score
		X̄	df	t-test	X̄	df	t-test
Nasion-menton height (mm)	7.5-10.5	114.29	6	−1.85	120.42	7	1.74	Male
	10.6-13.5	121.32	20	2.17	118.38	22	1.42	Female
	13.6-16.5	120.89	9	0.012	118.58	5	8.83	Male
ANS-Menton height (mm)	7.5-10.5	72.83	6	−0.58	75.62	7	1.44	Male
	10.6-13.5	73.06	20	−1.97	69.84	22	3.78	Male
	13.6-16.5	71.85	9	0.013	72.880	5	1.24	Male
Nasion-ANS height (mm)	7.5-10.5	52.1	6	0.12	50.89	7	−2.31	Female
	10.6-13.5	49.48	20	1.19	50.07	22	5.20	Male
	13.6-16.5	50.54	9	0.12	50.25	5	0.14	Male

ANS: Anterior nasal spine

The mean of the FMA for age group of 7.5–10.5, 10.6–13.5 and 13.6–16.5 (male and female) years was 34.87° and 34.6°; 32.41° and 34.78°; and 32.41° and 31.7°, respectively. The mean of the FMIA for age group of 7.5–10.5, 10.6–13.5, and 13.6–16.5 (male and female) years was 50.87° and 48.61°; 50.82° and 51.04°; and 49.53° and 46.3°, respectively. The mean of the IMPA for age group of 7.5–10.5, 10.6–13.5, and 13.6–16.5 (male and female) years was 96.67° and 98.08°; 95.59° and 93.1°; and 97.59° and 93.97°, respectively [Table 2].

Table 2

Results of one sample t-tests, by gender, and comparison of absolutes mean Z-scores between gender of tweed triangle in degrees

Variable	Age group	Male			Female			Sex with larger Z-score
		X̄	df	t-test	X̄	df	t-test
FMA (°)	7.5-10.5	34.87	6	1.26	34.6	7	0.11	Female
	10.6-13.5	32.41	20	−0.05	33.71	22	−1.37	Female
	13.6-16.5	34.78	9	2.38	31.7	5	0.023	Female
FMIA (°)	7.5-10.5	50.87	6	1.62	48.61	7	2.27	Male
	10.6-13.5	50.82	20	3.28	51.04	22	−0.68	Female
	13.6-16.5	49.53	9	0.031	46.3	5	0.87	Male
IMPA (°)	7.5-10.5	96.67	6	0.612	98.08	7	−1.85	Female
	10.6-13.5	95.59	20	−3.10	93.1	22	0.65	Female
	13.6-16.5	97.59	9	0.024	93.97	5	−1.85	Female

FMIA: Frankfort mandibular incisor angle, FMA: Frankfort mandibular plane, IMPA: Incisor mandibular plane angle

DISCUSSION

In the present study, all the subjects with sickle cell disease showed characteristic alteration in the craniofacial structure with variation in the morphometric measurements in comparison to the normal reference range. The majority of the patients in our study exhibited Angle's Class II malocclusion due to mandibular deficiency. Ferreira WB (2020) also stated similar findings in Craniofacial geometric morphometrics in the identification of patients with sickle cell anemia and sickle cell trait.[10]

Anterior facial height is reduced in our study sample probably as a corollary of underdeveloped lower portion of the face, resulting in a convex profile. Even the upper part of the face is under-developed; however, the results are not statistically significant. Our findings were in concordance with the findings of Maia NG et al., who evaluated 50 patients with sickle cell disease in the north of Minas Gerais, Brazil, for a subjective facial analysis and digital cephalometric analysis. 28 patients exhibited with reduced anterior facial height.[11]

The Tweed triangle displayed varied results in our study. The average FMA in normal individuals is 25°; however, in our study subjects, the angle was steeper. The average FMIA is 65°; however, in our subjects, the angle was reduced, which can be attributed to retrude mandibular incisors or downward and backward movement of the mandible resulting in increased overjet and overbite. The average IMPA in normal individuals is 90 degrees; however, it was statistically insignificant in our study. These findings were contrary to the findings of Shnorhokian et al., who examined 27 subjects with sickle cell disease and found that both the jaws were protrusive, whereas the incisors were reclined. They contemplated that excessive lip pressure might be responsible for reclination of the incisors.[12]

CONCLUSION

Sickle cell disease is allied to a variety of functional abnormalities namely mastication, swallowing, phonation, and breathing disorders along with an impending impact on the self-esteem of affected individuals. These abnormalities suggest a need for early diagnosis and appropriated treatment of dental malocclusion in this population, to render a better quality of life to these individuals. Further, it is recommended that these patients should have an access to orthodontic treatment in amalgamation with phonoaudiologic support to improve the quality of life.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.